Alternative titles; symbols
HGNC Approved Gene Symbol: SHOX
SNOMEDCT: 17818006, 38494008;
Cytogenetic location: Xp22.33 Genomic coordinates (GRCh38): X:624,344-659,411 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.33 | Langer mesomelic dysplasia | 249700 | Pseudoautosomal recessive | 3 |
| Leri-Weill dyschondrosteosis | 127300 | Pseudoautosomal dominant | 3 | |
| Short stature, idiopathic familial | 300582 | 3 |
Several studies had indicated the presence of one or more genes related to short stature in the pseudoautosomal region (PAR) (Zuffardi et al., 1982; Ballabio et al., 1989; Henke et al., 1991; Ogata et al. (1992, 1992); Ogata et al., 1995). Ellison et al. (1996) reported the isolation of a gene from the PAR which they suggested might be involved in the short stature of Turner syndrome. The gene product was thought to be a transcription factor, since the predicted protein contains a homeodomain similar to certain homeodomains found in a number of diverse organisms. Expression of the gene appeared to be restricted to osteogenic cells. It was expressed in trabecular bone cells and bone marrow stromal fibroblasts, while expression was not detected in a variety of other adult and fetal tissues. Ellison et al. (1996) named the gene PHOG for 'pseudoautosomal homeobox-containing osteogenic gene.' The Turner syndrome is presumably the result of haploinsufficiency of certain genes on the X chromosome. Gene dosage considerations lead to the prediction that the genes implicated are those that escape X inactivation and have functional Y homologs. Among the genes possessing these characteristics are those residing in the PAR. Genes in the PAR that are dosage sensitive probably contribute to the short stature observed in Turner syndrome. Ellison et al. (1997) elaborated on their work regarding the PHOG gene (Ellison et al., 1996).
From an interval of 170 kb of DNA within the pseudoautosomal region (PAR1) that was deleted in 36 individuals with short stature and different rearrangements on Xp22 or Yp11.3, Rao et al. (1997) isolated a homeobox-containing gene, referred to as SHOX by them, which has at least 2 alternatively spliced forms encoding proteins with different patterns of expression. They also identified a functionally significant SHOX mutation (312865.0001) by screening 91 individuals with idiopathic short stature. Data suggested an involvement of SHOX in idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients. The designation SHOX was derived from 'Short stature HOmeoboX-containing gene.' The 2 mRNAs identified by Rao et al. (1997) contained 1,870 (SHOXa) and 1,349 (SHOXb) nucleotides, which code for proteins of 292 and 225 amino acids, respectively. They showed that SHOX is highly conserved across species from mammals to fish and flies. Whereas expression of SHOXa was observed in skeletal muscle, placenta, pancreas, heart, and bone marrow fibroblasts, SHOXb transcripts were restricted to fetal kidney, skeletal muscle, and bone marrow fibroblasts, with the highest expression in bone marrow fibroblasts.
Rao et al. (1997) determined that the SHOX gene contains 6 exons ranging in size from 58 to 1,146 bp.
Fukami et al. (2006) reported that the putative SHOX enhancer revealed by the work of Benito-Sanz et al. (2005) and others may reside on an evolutionarily conserved sequence (ECS) of approximately 800 bp downstream of SHOX.
By fluorescence in situ hybridization studies of 4 patients with X-chromosomal rearrangements, 2 with normal height and 2 with short stature, Rao et al. (1997) narrowed the critical 'short stature interval' to a 270-kb region.
Rao et al. (1997) determined an interval of 170 kb of DNA within the pseudoautosomal region (PAR1) that was deleted in 36 individuals with short stature and different rearrangements on Xp22 or Yp11.3 (see SHOXY, 400020). This deletion was not detected in any of the relatives with normal stature or in a further 30 individuals with rearrangements on Xp22 or Yp11.3 with normal height. The SHOX gene was identified within this interval.
Clement-Jones et al. (2000) used in situ hybridization to analyze SHOX and SHOX2 (602504) expression during human embryonic development, and referenced the expression patterns against those of Og12x. The expression pattern of SHOX is more restricted than that of SHOX2, and is most evident in the midportion of limbs as well as the first and second pharyngeal arches. The authors proposed that SHOX expression in these sites provides evidence for the involvement of this gene in the development of other Turner stigmata beyond short stature, such as cubitus valgus, genu varum, high-arched palate, micrognathia, and sensorineural deafness. Their hypothesis was further supported by the presence of subtle Turner-characteristic dysmorphic skeletal features in some patients with SHOX nonsense mutations.
Rao et al. (2001) showed that the SHOX-encoded protein is located exclusively within the nucleus of a variety of stably-transfected cell lines, including U2OS, HEK293, COS-7, and NIH 3T3 cells. In contrast to this cell-type independent nuclear translocation, the transactivating potential of the SHOX protein on different luciferase reporter constructs was observed only in the osteogenic cell line U2OS. C-terminally truncated SHOX proteins, such as those associated with Leri-Weill syndrome (LWD; 127300), were inactive with regard to target gene activation. The authors hypothesized the existence of qualitative trait loci modulating SHOX activity in a cell-type specific manner.
Using microarray analysis, Marchini et al. (2007) showed that human osteosarcoma and chondrosarcoma cell lines carrying an inducible SHOX gene significantly upregulated NPPB (600295) expression upon SHOX induction. Chromatin immunoprecipitation and reporter gene assays confirmed that SHOX bound and activated the NPPB promoter. RT-PCR of human growth plate material showed coexpression of SHOX and NPPB, and immunohistochemical analysis showed that both proteins were expressed in late proliferative, prehypertrophic, and hypertrophic chondrocytes. Marchini et al. (2007) concluded that NPPB is a downstream effector of SHOX in bone.
Using U2OS osteosarcoma cells with inducible SHOX expression, Hristov et al. (2014) found that SHOX elevated cellular content of reactive oxygen and nitrogen species, induced lysosomal membrane rupture, and activated the intrinsic mitochondrial pathway of apoptosis. Lysosomal membrane rupture was accompanied by release of active cathepsin B (CTSB; 116810) to the cytosol and secretion of cathepsin B. Treatment with an antioxidant partly protected SHOX-expressing cells against lysosomal membrane rupture and apoptosis.
In the terminal pseudoautosomal pairing regions (PAR1) of Xp and Yp, approximately 2.6 Mb in length, there is an obligatory exchange during male meiosis that creates a male-specific recombination 'hot domain' with a recombination rate that is about 20 times higher than the genome average. Low-resolution analysis of PAR1 suggests that crossovers are distributed fairly randomly. By contrast, linkage disequilibrium and sperm crossover analyses indicated that crossovers in autosomal regions tend to cluster into 'hotspots' of 1-2 kb that lie between islands of disequilibrium of tens to hundreds of kilobases. To determine whether at high resolution this autosomal pattern also applies to PAR1, May et al. (2002) examined linkage disequilibrium over an interval of 43 kb around the SHOX gene. They showed that in northern European populations, disequilibrium decays rapidly with physical distance, which is consistent with this interval of PAR1 being recombinationally active in male meiosis. Analysis of a subregion of 9.9 kb in sperm showed, however, that crossovers are not distributed randomly, but instead cluster into an intense recombination hotspot that is very similar in morphology to autosomal hotspots. Thus, PAR1 crossover activity may be influenced by male-specific hotspots that are highly suitable for characterization by sperm DNA analysis.
Rao et al. (1997) reviewed evidence that the absence of the SHOX gene (its presence in single dose) may be responsible for the growth failure in Turner syndrome females. They pointed out that the growth pattern of the girl with idiopathic short stature (300582) in whom they demonstrated a point mutation (312865.0001) precisely followed the growth chart defined for Turner females. Turner females are frequently treated from early infancy until late puberty with pharmacologically high doses of growth hormone (139250), despite the absence of growth hormone deficiency. The authors commented that development of more specific therapy based on the SHOX gene should be a long-term goal.
Kosho et al. (1999) described the clinical features in 14 Japanese patients with partial monosomy of the short arm pseudoautosomal region involving SHOX (n = 11) or total monosomy of the pseudoautosomal region with no involvement of disease genes on the sex-differential regions (n = 3). Skeletal assessment showed that 3 patients had no discernible skeletal abnormalities, 1 patient exhibited short fourth metacarpals and borderline cubitus valgus, and the remaining 10 patients had Madelung deformity and/or mesomelia characteristic of Leri-Weill dyschondrosteosis (LWD; 127300), together with short fourth metacarpals and/or cubitus valgus. Skeletal lesions were more severe in females and became obvious with age. There was no correlation between the clinical phenotype and the deletion size. The authors concluded that haploinsufficiency of SHOX causes not only short stature but also Turner skeletal anomalies (such as short fourth metacarpals, cubitus valgus, and LWD) and that the growth pattern is primarily dependent on the presence or absence of LWD. Because skeletal lesions have occurred in a female-dominant and age-influenced fashion, it is inferred that estrogens exert a maturational effect on skeletal tissues that are susceptible to premature fusion of growth plates because of haploinsufficiency of SHOX, facilitating the development of skeletal lesions.
Dyschondrosteosis of Leri-Weill is an inherited skeletal dysplasia characterized by disproportionate short stature with predominantly mesomelic limb shortening and Madelung deformity of the arm. The disorder shows a dominant pedigree pattern and was thought to be autosomal dominant with a strong variability of expression between males and females. Attention was drawn to the pseudoautosomal region by observations of XY translocation in patients with this disorder by several authors including Pfeiffer (1980), Castillo et al. (1985), Kuznetzova et al. (1994), and Guichet et al. (1997). This prompted Belin et al. (1998) and Shears et al. (1998) to study linkage to markers in the pseudoautosomal region (PAR1) of the X and Y chromosomes. In 8 families with dyschondrosteosis (symbolized DCS by them), Belin et al. (1998) found linkage to microsatellite marker DXYS233 (maximum lod = 6.26 at theta = 0.0). Since the SHOX gene involved in idiopathic growth retardation and possibly the short stature of Turner syndrome maps to this region, they studied this gene and demonstrated large-scale deletions in 7 of the families and a nonsense mutation, arg195 to ter (R195X), in the eighth. In 1 extraordinarily informative family, a fetus with Langer mesomelic dysplasia (LMD; 249700) was found to have inherited from the mother a deletion involving the SHOX gene. Moreover, a second event, Turner syndrome, resulted in the loss of the other SHOX allele due to absence of the paternal X chromosome. Deletion of both SHOX alleles in the fetus was confirmed by fluorescence in situ hybridization; the DCS mother was found to be heterozygous at this locus. The pregnancy was terminated at 24 weeks.
In a 6-generation pedigree with Leri-Weill dyschondrosteosis, Shears et al. (1998) established linkage to DXYS6814 in the PAR1 region of the X and Y chromosomes (maximum lod = 6.28 at theta = 0.0). Linkage analysis of 3 smaller pedigrees increased the lod score to 8.68 (theta = 0.0). They identified submicroscopic PAR1 deletions encompassing the SHOX gene, segregating with the LWD phenotype, in 5 families. A point mutation (tyr199 to ter; 312865.0002) was predicted to produce a truncated protein lacking the terminal 94 amino acids (SHOXa) or 27 amino acids (SHOXb).
Spranger et al. (1999) observed a mother and her 5-year-old son, both with a terminal deletion of the short arm of the X chromosome. By molecular genetic analysis, the breakpoint was located distal to the steroid sulfatase gene (STS; 300747). The boy manifested, due to nullisomy of this region, short stature (related to the SHOX gene), chondrodysplasia punctata (related to the ARSE gene; 300180), and mental retardation (presumably related to the MRX49 locus; 300114). Short stature was present in both mother and son, and both also had bilateral Madelung deformity, a key feature of the Leri-Weill syndrome.
Grigelioniene et al. (2000) performed mutation analysis of the coding region of the SHOX gene in 18 patients with hypochondroplasia (146000) and found no mutations.
Schiller et al. (2000) studied 32 patients with Leri-Weill dyschondrosteosis from 18 different German and Dutch families and presented clinical, radiologic, and molecular data. Phenotypic manifestations were generally more severe in females. In males, muscular hypertrophy was a frequent finding. The authors identified submicroscopic deletions encompassing the SHOX gene in 10 of 18 families investigated. Deletion sizes varied between 100 kb and 9 Mb and did not correlate with the severity of the phenotype. They did not detect SHOX mutations in almost half (41%) of the LWD families studied.
Ogata et al. (2000) reported a Japanese female with 45,X[40%]/46,X, der(X)[60%], primary amenorrhea, and tall stature. She was confirmed to have complete gonadal dysgenesis at 19 years of age and was placed on hormone replacement therapy. Growth assessment revealed that she had a low normal height until her early teens but continued to grow with a nearly constant height velocity in her late teens, attaining a final height of 172 cm, which surpassed her target height range. FISH analysis showed that the der(X) chromosome was associated with duplication of roughly the distal half of Xp, including SHOX, and deletion of most of Xq. These results, in conjunction with the adult height data in 47,XXX, 46,XX gonadal dysgenesis, 47,XXY, 46,XY gonadal dysgenesis, and 46,X, idic(Xq-), suggested that the tall stature of this female was caused by the combined effects of SHOX duplication on the der(X) chromosome and gonadal estrogen deficiency. Furthermore, the similarity in the growth pattern between this female and patients with estrogen resistance or aromatase deficiency implied that the association of an extra copy of SHOX with gonadal estrogen deficiency may represent the further clinical entity for tall stature resulting from continued growth in late teens or into adulthood.
Huber et al. (2001) studied 8 families with the dyschondrosteosis phenotype and reported point mutations in the SHOX gene in 5 and deletions in 3. The point mutations comprised 4 nonsense and a missense mutation resulting in replacement of an arginine residue with cysteine (312865.0007). Combined with the results of their previous work (Belin et al., 1998), 10 of 16 families with this phenotype had deletions of the SHOX gene while 6 of 16 had point mutations.
LWD can be defined genetically by haploinsufficiency of the SHOX gene. Ross et al. (2001) studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, ages 3 to 56 years) with confirmed SHOX abnormalities. SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). In the LWD subjects, height deficits ranged from -4.6 to +0.6 SD (mean +/- SD = -2.2 +/- 1.0). There were no statistically significant effects on age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD is approximately two-thirds that of Turner syndrome. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of the Madelung deformity was higher in the LWD versus a Turner syndrome population. The prevalence of increased carrying angle, high-arched palate, and scoliosis was similar in the 2 populations.
Rappold et al. (2002) investigated the incidence and type of SHOX mutations in patients with short stature. They analyzed the SHOX gene for intragenic mutations by SSCP, followed by sequencing, in 750 patients and for complete gene deletions by FISH in 150 patients (900 patients total). All patients had a normal karyotype, and their heights for chronologic age were below the 3rd percentile or -2 SD of national height standards. All were without obvious skeletal features reminiscent of Leri-Weill syndrome at the time of diagnosis. Silent, missense, and nonsense mutations and a small deletion in the coding region of SHOX were identified in 9 of the 750 patients analyzed for intragenic mutations. Complete gene deletions were detected in 3 of the 150 patients studied for gene deletions. At least 3 of the 9 intragenic mutations were judged to be functional based upon the genotype-phenotype relationship for the parents and normal control individuals. The authors concluded that 2.4% of children with short stature have SHOX mutations and that the spectrum of mutations is biased, with the vast majority leading to complete gene deletions.
Niesler et al. (2002) described an online human SHOX mutation database that contained 29 unique intragenic mutations that had been detected in 39 unrelated patients. Not included in the database were complete SHOX gene deletions, which represent the majority of detectable SHOX mutations (Rappold et al., 2002).
In a man with Langer mesomelic dysplasia (249700), Zinn et al. (2002) identified a hemizygous or homozygous 1-bp insertion (312865.0009) in exon 6a of the SHOX gene, causing a frameshift that replaced the C terminus with 50 novel amino acids, deleting a putative SH3-binding site. Zinn et al. (2002) concluded that the SHOXa isoform is essential for normal skeletal development.
Morizio et al. (2003) performed fluorescence in situ hybridization in 56 patients with short stature of unknown cause and found deletion of the SHOX gene in 4 patients (7.1%). No skeletal abnormalities were detected in these patients either on physical examination or by x-rays of the upper and lower limbs.
Thomas et al. (2004) described a family in which several members and a fetus had mutations in the SHOX gene. The grandmother, mother, and uncle all carried an approximately 200-kb interstitial deletion that included the entire SHOX gene. Their condition was mild, with no Madelung deformity, and was originally diagnosed as hypochondroplasia (146000). This deletion was transmitted to the fetus, who also inherited an additional Xp deletion (Xpter-p22.12) that included the SHOX gene from her chromosomally normal father. The ultrasound scan of the fetus and subsequent autopsy findings were consistent with Langer mesomelic dysplasia.
Binder et al. (2004) sought to determine the prevalence of SHOX mutations in Leri-Weill dyschondrosteosis and investigated the degree of growth failure in relation to mutation, sex, age of menarche, and wrist deformity. In 14 of 20 families (70%), SHOX mutations were detected, with 7 deletions (4 de novo) and 7 point mutations (1 de novo). The latter included 5 missense mutations of the SHOX homeodomain, 1 nonsense mutation truncating the whole homeodomain (E102X; 312865.0011), and 1 point mutation causing a C-terminal elongation of SHOX (X293R; 312865.0012). The authors concluded that SHOX defects were the main cause of Leri-Weill dyschondrosteosis. Growth failure occurred during the first years of life with a mean height loss of 2.16 standard deviations whereas pubertal growth may only be mildly or not affected. Children with a severe degree of wrist deformity were significantly shorter than those with mild deformities. The effect of growth hormone (139250) therapy varied among individuals.
Schneider et al. (2005) analyzed 118 unrelated patients with Leri-Weill dyschondrosteosis and more than 1,500 patients with idiopathic short stature for deletions encompassing SHOX. They detected deletions in 34% of the patients with Leri-Weill dyschondrosteosis and in 2% of the patients with idiopathic short stature. In 27 patients with Leri-Weill dyschondrosteosis and in 6 with idiopathic short stature, detailed deletion mapping was performed by PCR using pseudoautosomal polymorphic markers and by fluorescence in situ hybridization with the use of cosmid clones. Schneider et al. (2005) showed that, although the identified deletion varied in size, most (73%) patients tested shared a distinct proximal deletion breakpoint. They proposed that the sequence present within this proximal deletion breakpoint 'hotspot' region predisposes to recurrent breaks.
Schneider et al. (2005) studied 9 missense mutations in the homeodomain of the SHOX gene of patients with idiopathic short stature and LWD and demonstrated loss of DNA binding, reduced dimerization ability, and/or impaired nuclear translocation in 8 of the mutations. The remaining R153L mutation (312865.0005) was defective in transcriptional activation even though it was still able to bind to DNA, dimerize, and translocate to the nucleus. Schneider et al. (2005) concluded that single missense mutations in the homeodomain fundamentally impair key SHOX functions, thus causing the phenotypes of short stature and LWD.
Zinn et al. (2006) studied deletions of SHOX in Leri-Weill dyschondrosteosis ascertained by Ross et al. (2001). Their results differed markedly from those reported by Schneider et al. (2005). They found a recombination hotspot several hundred kilobases proximal to the hotspot reported by Schneider et al. (2005). The reason for this discrepancy was unclear.
Defects in SHOX had been identified in approximately 60% of LWD cases, whereas in the remaining cases the molecular basis was unknown. This suggested either heterogeneity or the presence of mutations in unanalyzed regions of SHOX, such as the upstream, intragenic, or downstream regulatory sequences. Therefore, using a new panel of microsatellite markers, Benito-Sanz et al. (2005) screened for deletions in the pseudoautosomal region 1 (PAR1) of 80 patients with LWD in whom SHOX deletions and mutations had been excluded. They identified 12 patients with LWD who presented with a novel class of PAR1 deletions that did not include the SHOX gene. The deletions were of variable size and mapped at least 30 to 530 kb downstream of SHOX. This type of deletion accounted for 15% of the patients. In all cases, the deletions cosegregated with the phenotype. No apparent phenotypic differences were observed between patients with SHOX deletions and those with this new class of PAR1 deletions. Thus, they identified a second PAR1 region implicated in the etiopathogenesis of LWD. The findings indicated the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development. Benito-Sanz et al. (2005) suggested that deletion analysis of this region should be included in the mutation screening of patients with LWD, Langer mesomelic dysplasia (LMD; 249700), and idiopathic short stature (ISS).
Benito-Sanz et al. (2006) characterized the SHOX deletion limits in a cohort of 47 European patients with LWD and 1 with Langer mesomelic dysplasia. They detected a high level of genetic heterogeneity of SHOX deletions in patients with LWD/LMD who had a significant proportion of deletions extending beyond the PAR1 boundary. No recombination hotspots were identified.
Rappold et al. (2007) identified mutations or deletions in the SHOX gene in 68 (4.2%) of 1,608 unrelated prepubertal children with sporadic or familial short stature from various countries, including 32 (58%) of 55 diagnosed with Leri-Weill dyschondrosteosis and 34 (2.2%) of 1,534 diagnosed with idiopathic short stature. Two patients were not classified. The gene changes included complete deletions (70.6% of cases), partial deletions (5.9%), and point mutations (23.5%). Although mean height standard deviation scores did not differ between those with nonsyndromic short stature with or without SHOX mutations, those with SHOX mutations had a higher frequency of certain bone deformities and dysmorphic signs, such as short forearm and lower leg, cubitus valgus, Madelung deformity, high-arched palate, and muscular hypertrophy.
For the identification and characterization of SHOX deletions in 15 patients with Leri-Weill dyschondrosteosis, Gatta et al. (2007) used multiple ligation probe amplification (MLPA) assay. Heterozygous deletion of SHOX was demonstrated in 7 patients, and 2 different proximal breakpoints were disclosed. In 3 of the patients who carried chromosome abnormalities, MLPA analysis identified the chromosomal rearrangement, showing, in addition to the SHOX deletions, the gain or loss of other genes mapped on the X and Y chromosomes. Gatta et al. (2007) pointed out that the MLPA analysis can be carried out on a buccal swab, and that this technique represents a fast, simple, and high throughput approach in the screening of SHOX deletions. It may provide more information than FISH or microsatellite analysis of intragenic CA repeats.
Bleyl et al. (2007) reported a mother and son with anterior segment eye abnormalities and an unusual skeletal phenotype intermediate between LWD and LMD. The mother, who was previously described by Kivlin et al. (1993), was found to have a 46,X,inv(X)(p22.3q27) pericentric inversion of the X chromosome; her son had a resultant 46,Y,rec(X)dup(Xq)inv(X)(p22.3q27) recombinant X chromosome. Array CGH mapping localized the Xp22.33 breakpoint to 30 to 68 kb 5-prime of the SHOX gene, suggesting that the skeletal dysplasia in both mother and son was allelic to LWD and LMD and resulted from misexpression of SHOX. The Xq27.1 breakpoint, approximately 90 kb 3-prime of the SOX3 gene (313430), was presumably responsible for the anterior chamber abnormalities.
In 12 Spanish multiplex families with LWD or LMD, Barca-Tierno et al. (2011) identified heterozygosity or homozygosity, respectively, for an A170P mutation (312865.0014) in the SHOX gene. Microsatellite analysis revealed a shared haplotype around SHOX, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the 12 families were of that ethnic group. Another mutation at the same location, A170D (312865.0015), was identified in 2 unrelated non-Gypsy Spanish families with LWD.
Deletions of the SHOX Downstream Regulatory Domain
Bertorelli et al. (2007) reported a fetus, conceived of consanguineous parents, with Langer mesomelic dysplasia resulting from a homozygous deletion extending from exon 6b of the SHOX gene downstream for 1.1 Mb and encompassing a cis-acting enhancer region (312865.0013). Both parents, who were heterozygous for the mutation, had Leri-Weill syndrome.
Sabherwal et al. (2007) analyzed the DNA of 122 patients with clinical manifestations of LWD, and identified an intragenic mutation in 17 and deletion of the entire gene in 47; further screening identified 4 families with an intact SHOX coding region who had microdeletions in the 3-prime pseudoautosomal region, with a common deletion interval of approximately 200 kb that segregated with disease in each family. Comparative genetic analysis revealed 8 highly conserved noncoding DNA elements (CNE2 to CNE9) within this interval, located between 48 and 215 kb downstream of the SHOX gene, and functional analysis showed that CNE4, CNE5, and CNE9 had cis-regulatory activity in the developing limbs of chicken embryos. Sabherwal et al. (2007) stated that their findings indicated that the deleted region in the affected families contains several distinct elements that regulate SHOX expression in the developing limb, and noted that deletion of these elements in humans with both SHOX genes intact generates a phenotype apparently indistinguishable from that of patients with mutations in the SHOX coding region.
Chen et al. (2009) analyzed copy number variation in the pseudoautosomal region of the sex chromosomes in 735 individuals with idiopathic short stature (ISS) and in 58 patients with Leri-Weill syndrome. They identified 31 microdeletions in the pseudoautosomal region in ISS patients, 8 of which involved only enhancer CNEs (CNE7, CNE8, and CNE9) residing at least 150 kb centromeric to the SHOX gene. In the Leri-Weill syndrome patients, 29 microdeletions were identified, 13 of which involved CNEs and left the SHOX gene intact. These deletions were not found in 100 controls. Chen et al. (2009) concluded that enhancer deletions in the SHOX downstream region are a relatively frequent cause of growth failure in patients with idiopathic short stature and Leri-Weill syndrome.
Rao et al. (1997) searched for small rearrangements or point mutations in the SHOX gene in 91 unrelated male and female patients with idiopathic short stature (300582), defined as height 2 standard deviations or more below the mean. They designed 6 sets of PCR primers to amplify not only single exons but also sequences flanking the exons and a small part of the 5-prime untranslated region. In 1 individual of European descent, Rao et al. (1997) identified a 674C-T transition in exon 5, resulting in an arg195-to-ter (R195X) substitution and a truncated protein lacking the highly conserved 3-prime region. The mutation was absent in 300 chromosomes from normal whites. In the pedigree of the proband, all 5 individuals with short stature showed an aberrant SSCP shift and the R195X substitution. Affected members were found in 3 generations.
In a family with Leri-Weill dyschondrosteosis (LWD; 127300) in 3 generations, Shears et al. (1998) demonstrated a C-to-G point mutation at nucleotide 688, converting TAC (tyr) to TAG (stop). The mutation produced a truncated protein lacking the terminal 94 amino acids (SHOXa) or 27 amino acids (SHOXb).
In a fetus with Langer mesomelic dysplasia (LMD; 249700), Belin et al. (1998) confirmed deletion of both SHOX alleles by fluorescence in situ hybridization. The mother, who had Leri-Weill dyschondrosteosis (LWD; 127300), was found to be heterozygous at this locus. Belin et al. (1998) showed that Langer mesomelic dysplasia results from homozygous mutations at the SHOX locus. Shears et al. (1998) likewise demonstrated a role for homozygous deletion involving the SHOX gene in the etiology of Langer dysplasia.
In a male infant with Langer mesomelic dysplasia, Ogata et al. (2002) found nullizygosity for SHOX. FISH analysis showed loss of SHOX from the Y chromosome of the infant and from the X chromosome of his father, demonstrating heterozygous SHOX deletion in the 2 males. The infant also carried a missense mutation in the homeobox domain in exon 4 (312865.0008). The father had mild Leri-Weill dyschondrosteosis.
In a woman with Langer mesomelic dysplasia, Zinn et al. (2002) identified a complete deletion of one SHOX allele and a frameshift (312865.0010) in the other allele that truncates the protein after only 13 amino acids of the homeodomain, likely making her homozygous null for SHOX.
In a patient with Leri-Weill dyschondrosteosis (127300), Grigelioniene et al. (2000) identified a 485C-G transversion in the SHOX gene, resulting in a leu132-to-val amino acid substitution.
In a patient with Leri-Weill dyschondrosteosis (127300), Grigelioniene et al. (2000) identified a 549G-T transversion in the SHOX gene, resulting in an arg153-to-leu (R153L) amino acid substitution.
Using U2OS cells expressing inducible SHOX constructs, Hristov et al. (2014) found that, in contrast with wildtype, SHOX with the R153L mutation did not induce apoptosis, oxidative stress, or lysosomal membrane rupture.
In a patient with Leri-Weill dyschondrosteosis (127300), Grigelioniene et al. (2000) identified a deletion of 1272G of the SHOX gene, resulting in a premature stop codon at position 75 of the amino acid sequence.
In a family with dyschondrosteosis (127300), Huber et al. (2001) detected a C-to-T transition at nucleotide 517 of the SHOX gene, resulting in a substitution of cysteine for arginine at residue 173 (R173C). The substitution occurs in a highly conserved region of the recognition helix of the homeodomain.
Shears et al. (2002) studied a consanguineous Spanish family in which the father and maternal grandmother had Leri-Weill dyschondrosteosis and a newborn male and his mother had Langer mesomelic dysplasia (249700), leading to a 'pseudodominant' inheritance pattern. The SHOX R173C mutation was identified in homozygous state in the mother and child and in heterozygous state in the father and grandmother.
Ogata et al. (2002) reported the clinical and molecular findings in a Japanese family consisting of a male infant with SHOX nullizygosity and his 4 family members with SHOX haploinsufficiency. The male infant had Langer mesomelic dysplasia (249700), the prepubertal sister had idiopathic short stature phenotype with no discernible skeletal features, the father had mild Leri-Weill dyschondrosteosis (127300), and the mother and the maternal grandmother had moderate Leri-Weill dyschondrosteosis. The 5 subjects lacked clinically recognizable short metacarpals, cubitus valgus, high-arched palate, short neck, and micrognathia, as well as recurrent otitis media and hearing loss. Fluorescence in situ hybridization and sequence analyses showed that the proband had a pseudoautosomal microdeletion involving SHOX (312865.0003) and a 502C-T transition in the homeobox domain at exon 4 that resulted in an arg-to-trp missense mutation at codon 168 (R168W). The father was heterozygous for the SHOX deletion, and the sister, the mother, and the grandmother were heterozygous for the C502T mutation. The authors concluded that these results, in conjunction with the previous findings, suggest that mesomelic skeletal features such as Langer mesomelic dysplasia and Leri-Weill dyschondrosteosis, which are absent or rare in Turner syndrome, are primarily caused by SHOX dosage effect and the bone maturing effect of gonadal estrogens, whereas other skeletal features such as short metacarpals, cubitus valgus, and various craniofacial and cervical skeletal stigmata, which are common in Turner syndrome, are largely contributed by a compressive effect of distended lymphatics and lymphedema on the developing skeletal tissues.
In a man with Langer mesomelic dysplasia (249700), Zinn et al. (2002) found a hemizygous or homozygous insertion of a C (723insC) in a stretch of 6 C's in exon 6a of the SHOX gene. The insertion causes a frameshift that replaces the C terminus with 50 novel amino acids, deleting a putative SH3 binding site. Zinn et al. (2002) concluded that the SHOXa isoform is essential for normal skeletal development.
In a woman with Langer mesomelic dysplasia (249700), Zinn et al. (2002) identified a complete deletion of one SHOX allele (312865.0003) and a 2-bp insertion (350insAG) causing a frameshift in the other allele that truncates the protein after only 13 amino acids of the homeodomain, likely making her homozygous null for SHOX. Parental studies showed that her father was heterozygous for the frameshift mutation.
In 2 sibs with Leri-Weill dyschondrosteosis (127300) and their affected father, Binder et al. (2004) detected a G-to-T transversion at nucleotide 304 in exon 3 of the SHOX gene that resulted in premature termination of the protein at glutamine-102 (E102X). The truncation was predicted to result in total loss of the homeodomain.
In a boy with Leri-Weill dyschondrosteosis (127300) and his affected mother, Binder et al. (2004) found a T-to-C transition at nucleotide 877 of the SHOX gene that affected the stop codon (X293R). The mutation was predicted to elongate the SHOX protein with the addition of 48 C-terminal amino acids.
Bertorelli et al. (2007) reported a fetus, conceived of consanguineous parents, with Langer mesomelic dysplasia (249700) resulting from a homozygous deletion extending from exon 6b of the SHOX gene downstream for 1.1 Mb and encompassing a cis-acting enhancer region. Both parents, who were heterozygous for the deletion, had features of classic Leri-Weill syndrome (127300). A previous fetus with features of Langer mesomelic dysplasia was also found to be homozygous for the mutation. Initial conventional gene testing for SHOX mutations in the parents did not reveal any mutations, and subsequent deletion analysis was carried out by multiplex ligation-dependent probe amplification.
In 34 individuals with Leri-Weill dyschondrosteosis (127300) and 4 with Langer mesomelic dysplasia (249700) from 12 Spanish multiplex families, 2 of which had previously been studied (Sabherwal et al. (2004, 2004)), Barca-Tierno et al. (2011) identified heterozygosity or homozygosity, respectively, for a 508G-C transversion in the SHOX gene, resulting in an ala170-to-pro (A170P) substitution. Microsatellite analysis revealed a shared haplotype around SHOX, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the 12 families were of that ethnic group. The mutation was not found in 359 Eastern European Gypsies. Transient transfection studies in U2OS cells demonstrated that the A170P mutant protein failed to localize to the nucleus. Expression of mutant SHOX in the human growth plate of a 22-week-old fetus homozygous for A170P was compared to that of a 23-week-old normal fetal growth plate: SHOX was observed in the resting, proliferative, and hypertrophic zones of both the control and the LMD growth plate. However, chondrocytes were enlarged and in pairs in the reserve zone of the LMD growth plate, and their columnar stacking in the proliferative zone was disorganized, with the chondrocytes appearing in less-defined columns and in smaller clusters.
In affected individuals from 2 unrelated non-Gypsy Spanish families with Leri-Weill dyschondrosteosis (127300), Barca-Tierno et al. (2011) identified heterozygosity for a 509C-A transversion in the SHOX gene, resulting in an ala170-to-asp (A170D) substitution. No common SHOX haplotype was observed.
Benito-Sanz et al. (2012) identified the same 47,543-bp deletion (chrX:700,549-748,093, GRCh37) in the pseudoautosomal region 1 (PAR1) downstream of the SHOX gene in 19 of 124 probands with Leri-Weill dyschondrosteosis (127300) (15.3%) and 11 of 576 probands with idiopathic short stature (300582) (1.9%). Eight evolutionarily conserved regions (ECRs) were identified within the deleted sequence, and all ECRs were evaluated for SHOX regulatory activity. Chromosome conformation capture assays in embryonic chicken limbs demonstrated that ECR1 interacts with a sequence close to or within the SHOX proximal promoter. Luciferase reporter assays confirmed that ECR1 operates as an orientation- and position-independent enhancer.
Ballabio, A., Bardoni, B., Carrozzo, R., Andria, G., Bick, D., Campbell, L., Hamel, B., Ferguson-Smith, M. A., Gimelli, G., Fraccaro, M., Maraschio, P., Zuffardi, O., Guioli, S., Camerino, G. Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome. Proc. Nat. Acad. Sci. 86: 10001-10005, 1989. [PubMed: 2602357] [Full Text: https://doi.org/10.1073/pnas.86.24.10001]
Barca-Tierno, V., Aza-Carmona, M., Barroso, E., Heine-Suner, D., Azmanov, D., Rosell, J., Ezquieta, B., Montane, L. S., Vendrell, T., Cruz, J., Santos, F., Rodriguez, J. I., Pozo, J., Argente, J., Kalaydjieva, L., Gracia, R., Campos-Barros, A., Benito-Sanz, S., Heath, K. E. Identification of a Gypsy SHOX mutation (p.A170P) in Leri-Weill dyschondrosteosis and Langer mesomelic dysplasia. Europ. J. Hum. Genet. 19: 1218-1225, 2011. [PubMed: 21712857] [Full Text: https://doi.org/10.1038/ejhg.2011.128]
Belin, V., Cusin, V., Viot, G., Girlich, D., Toutain, A., Moncla, A., Vekemans, M., Le Merrer, M., Munnich, A., Cormier-Daire, V. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nature Genet. 19: 67-69, 1998. [PubMed: 9590292] [Full Text: https://doi.org/10.1038/ng0198-67]
Benito-Sanz, S., Gorbenko del Blanco, D., Huber, C., Thomas, N. S., Aza-Carmona, M., Bunyan, D., Maloney, V., Argente, J., Cormier-Daire, V., Campos-Barros, A., Heath, K. E. Characterization of SHOX deletions in Leri-Weill dyschondrosteosis (LWD) reveals genetic heterogeneity and no recombination hotspots. (Letter) Am. J. Hum. Genet. 409-414, 2006. [PubMed: 16826534] [Full Text: https://doi.org/10.1086/506390]
Benito-Sanz, S., Royo, J. L., Barroso, E., Paumard-Hernandez, B., Barreda-Bonis, A. C., Liu, P., Gracia, R., Lupski, J. R., Campos-Barros, A., Gomez-Skarmeta, J. L., Heath, K. E. Identification of the first recurrent PAR1 deletion in Leri-Weill dyschondrosteosis and idiopathic short stature reveals the presence of a novel SHOX enhancer. J. Med. Genet. 49: 442-450, 2012. [PubMed: 22791839] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100678]
Benito-Sanz, S., Thomas, N. S., Huber, C., Gorbenko del Blanco, D., Aza-Carmona, M., Crolla, J. A., Maloney, V., Rappold, G., Argente, J., Campos-Barros, A., Cormier-Daire, V., Heath, K. E. A novel class of pseudoautosomal region 1 deletions downstream of SHOX is associated with Leri-Weill dyschondrosteosis. Am. J. Hum. Genet. 77: 533-544, 2005. Note: Erratum: Am. J. Hum. Genet. 77: 1131 only, 2005. [PubMed: 16175500] [Full Text: https://doi.org/10.1086/449313]
Bertorelli, R., Capone, L., Ambrosetti, F., Garavelli, L., Varriale, L., Mazza, V., Stanghellini, I., Percesepe, A., Forabosco, A. The homozygous deletion of the 3-prime enhancer of the SHOX gene causes Langer mesomelic dysplasia. (Letter) Clin. Genet. 72: 490-491, 2007. [PubMed: 17935511] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00875.x]
Binder, G., Renz, A., Martinez, A., Keselman, A., Hesse, V., Riedl, S. W., Hausler, G., Fricke-Otto, S., Frisch, H., Heinrich, J. J., Ranke, M. B. SHOX haploinsufficiency and Leri-Weill dyschondrosteosis: prevalence and growth failure in relation to mutation, sex, and degree of wrist deformity. J. Clin. Endocr. Metab. 89: 4403-4408, 2004. [PubMed: 15356038] [Full Text: https://doi.org/10.1210/jc.2004-0591]
Bleyl, S. B., Byrne, J. L. B., South, S. T., Dries, D. C., Stevenson, D. A., Rope, A. F., Vianna-Morgante, A. M., Schoenwolf, G. C., Kivlin, J. D., Brothman, A., Carey, J. C. Brachymesomelic dysplasia with Peters anomaly of the eye results from disruptions of the X chromosome near the SHOX and SOX3 genes. Am. J. Med. Genet. 143A: 2785-2795, 2007. [PubMed: 17994562] [Full Text: https://doi.org/10.1002/ajmg.a.32036]
Castillo, S., Youlton, R., Be, C. Dyschondrosteosis is controlled by X and Y linked loci. (Abstract) Cytogenet. Cell Genet. 40: 601-602, 1985.
Chen, J., Wildhardt, G., Zhong, Z., Roth, R., Weiss, B., Steinberger, D., Decker, J., Blum, W. F., Rappold, G. Enhancer deletions of the SHOX gene as a frequent cause of short stature: the essential role of a 250 kb downstream regulatory region. J. Med. Genet. 46: 834-839, 2009. [PubMed: 19578035] [Full Text: https://doi.org/10.1136/jmg.2009.067785]
Clement-Jones, M., Schiller, S., Rao, E., Blaschke, R. J., Zuniga, A., Zeller, R., Robson, S. C., Binder, G., Glass, I., Strachan, T., Lindsay, S., Rappold, G. A. The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum. Molec. Genet. 9: 695-702, 2000. [PubMed: 10749976] [Full Text: https://doi.org/10.1093/hmg/9.5.695]
Ellison, J. W., Wardak, Z., Webster, M., Chiong, W. PHOG, a candidate gene for involvement in the short stature of Turner syndrome. (Abstract) Am. J. Hum. Genet. 59 (suppl.): A32, 1996.
Ellison, J. W., Wardak, Z., Young, M. F., Robey, P. G., Webster, M., Chiong, W. PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum. Molec. Genet. 6: 1341-1347, 1997. [PubMed: 9259282] [Full Text: https://doi.org/10.1093/hmg/6.8.1341]
Fukami, M., Kato, F., Tajima, T., Yokoya, S., Ogata, T. Transactivation function of an approximately 800-bp evolutionarily conserved sequence at the SHOX 3-prime region: implication for the downstream enhancer. (Letter) Am. J. Hum. Genet. 78: 167-170, 2006. [PubMed: 16385461] [Full Text: https://doi.org/10.1086/499254]
Gatta, V., Antonucci, I., Morizio, E., Palka, C., Fischetto, R., Mokini, V., Tumini, S., Calabrese, G., Stuppia, L. Identification and characterization of different SHOX gene deletions in patients with Leri-Weill dyschondrosteosys (sic) by MLPA assay. J. Hum. Genet. 52: 21-27, 2007. [PubMed: 17091221] [Full Text: https://doi.org/10.1007/s10038-006-0074-5]
Grigelioniene, G., Eklof, O., Ivarsson, S. A., Westphal, O., Neumeyer, L., Kedra, D., Dumanski, J., Hagenas, L. Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia. Hum. Genet. 107: 145-149, 2000. [PubMed: 11030412] [Full Text: https://doi.org/10.1007/s004390000352]
Guichet, A., Briault, S., Le Merrer, M., Moraine, C. Are t(X;Y) (p22;q11) translocations in females frequently associated with Madelung deformity? Clin. Dysmorph. 6: 341-345, 1997. [PubMed: 9354843] [Full Text: https://doi.org/10.1097/00019605-199710000-00007]
Henke, A., Wapenaar, M., van Ommen, G.-J., Maraschio, P., Camerino, G., Rappold, G. Deletions within the pseudoautosomal region help map three new markers and indicate a possible role of this region in linear growth. Am. J. Hum. Genet. 49: 811-819, 1991. [PubMed: 1897527]
Hristov, G., Marttila, T., Durand, C., Niesler, B., Rappold, G. A. SHOX triggers the lysosomal pathway of apoptosis via oxidative stress. Hum. Molec. Genet. 23: 1619-1630, 2014. [PubMed: 24186869] [Full Text: https://doi.org/10.1093/hmg/ddt552]
Huber, C., Cusin, V., Le Merrer, M., Mathieu, M., Sulmont, V., Dagoneau, N., Munnich, A., Cormier-Daire, V. SHOX point mutations in dyschondrosteosis. J. Med. Genet. 38: 323 only, 2001. [PubMed: 11403039] [Full Text: https://doi.org/10.1136/jmg.38.5.323]
Kivlin, J. D., Carey, J. C., Richey, M. A. Brachymesomelia and Peters anomaly: a new syndrome. Am. J. Med. Genet. 45: 416-419, 1993. [PubMed: 8465841] [Full Text: https://doi.org/10.1002/ajmg.1320450403]
Kosho, T., Muroya, K., Nagai, T., Fujimoto, M., Yokoya, S., Sakamoto, H., Hirano, T., Terasaki, H., Ohashi, H., Nishimura, G., Sato, S., Matsuo, N., Ogata, T. Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of Turner syndrome. J. Clin. Endocr. Metab. 84: 4613-4621, 1999. [PubMed: 10599728] [Full Text: https://doi.org/10.1210/jcem.84.12.6289]
Kuznetzova, T., Baranov, A., Ivaschenko, T., Savitsky, G. A., Lanceva, O. E., Wang, M. R., Giollant, M., Malet, P., Kascheeva, T., Vakharlovsky, V., Baranov, V. S. X;Y translocation in a girl with short stature and some features of Turner's syndrome: cytogenetic and molecular studies. J. Med. Genet. 31: 649-651, 1994. [PubMed: 7815426] [Full Text: https://doi.org/10.1136/jmg.31.8.649]
Marchini, A., Hacker, B., Marttila, T., Hesse, V., Emons, J., Weiss, B., Karperien, M., Rappold, G. BNP is a transcriptional target of the short stature homeobox gene SHOX. Hum. Molec. Genet. 16: 3081-3087, 2007. [PubMed: 17881654] [Full Text: https://doi.org/10.1093/hmg/ddm266]
May, C. A., Shone, A. C., Kalaydjieva, L., Sajantila, A., Jeffreys, A. J. Crossover clustering and rapid decay of linkage disequilibrium in the Xp/Yp pseudoautosomal gene SHOX. Nature Genet. 31: 272-275, 2002. [PubMed: 12089524] [Full Text: https://doi.org/10.1038/ng918]
Morizio, E., Stuppia, L., Gatta, V., Fantasia, D., Guanciali Franchi, P., Rinaldi, M. M., Scarano, G., Concolino, D., Giannotti, A., Verrotti, A., Chiarelli, F., Calabrese, G., Palka, G. Deletion of the SHOX gene in patients with short stature of unknown cause. Am. J. Med. Genet. 119A: 293-296, 2003. [PubMed: 12784295] [Full Text: https://doi.org/10.1002/ajmg.a.20198]
Niesler, B., Fischer, C., Rappold, G. A. The human SHOX mutation database. Hum. Mutat. 20: 338-341, 2002. [PubMed: 12402330] [Full Text: https://doi.org/10.1002/humu.10125]
Ogata, T., Goodfellow, P., Petit, C., Aya, M., Matsuo, N. Short stature in a girl with a terminal Xp deletion distal to DXYS15: localisation of a growth gene(s) in the pseudoautosomal region. J. Med. Genet. 29: 455-459, 1992. [PubMed: 1640423]
Ogata, T., Kosho, T., Wakui, K., Fukushima, Y., Yoshimoto, M., Miharu, N. Short stature homeobox-containing gene duplication on the der(X) chromosome in a female with 45,X/46,X, der(X), gonadal dysgenesis, and tall stature. J. Clin. Endocr. Metab. 85: 2927-2930, 2000. [PubMed: 10946905] [Full Text: https://doi.org/10.1210/jcem.85.8.6745]
Ogata, T., Muroya, K., Sasaki, G., Nishimura, G., Kitoh, H., Hattori, T. SHOX nullizygosity and haploinsufficiency in a Japanese family: implication for the development of Turner skeletal features. J. Clin. Endocr. Metab. 87: 1390-1394, 2002. [PubMed: 11889214] [Full Text: https://doi.org/10.1210/jcem.87.3.8348]
Ogata, T., Petit, C., Rappold, G., Matsuo, N., Matsumoto, T., Goodfellow, P. Chromosomal localisation of a pseudoautosomal growth gene(s). J. Med. Genet. 29: 624-628, 1992. [PubMed: 1404292] [Full Text: https://doi.org/10.1136/jmg.29.9.624]
Ogata, T., Yoshizawa, A., Muroya, K., Matsuo, N., Fukushima, Y., Rappold, G., Yokoya, S. Short stature in a girl with partial monosomy of the pseudoautosomal region distal to DXYS15: further evidence for the assignment of the critical region for a pseudoautosomal growth gene(s). J. Med. Genet. 32: 831-834, 1995. [PubMed: 8558568] [Full Text: https://doi.org/10.1136/jmg.32.10.831]
Pfeiffer, R. A. Observations in a case of an X/Y translocation, t(X;Y)(p22;q11), in a mother and son. Cytogenet. Cell Genet. 26: 150-157, 1980. [PubMed: 7389410] [Full Text: https://doi.org/10.1159/000131436]
Rao, E., Blaschke, R. J., Marchini, A., Niesler, B., Burnett, M., Rappold, G. A. The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator. Hum. Molec. Genet. 10: 3083-3091, 2001. [PubMed: 11751690] [Full Text: https://doi.org/10.1093/hmg/10.26.3083]
Rao, E., Weiss, B., Fukami, M., Mertz, A., Meder, J., Ogata, T., Heinrich, U., Garcia-Heras, J., Schiebel, K., Rappold, G. A. FISH-deletion mapping defines a 270-kb short stature critical interval in the pseudoautosomal region PAR1 on human sex chromosomes. Hum. Genet. 100: 236-239, 1997. [PubMed: 9254856] [Full Text: https://doi.org/10.1007/s004390050497]
Rao, E., Weiss, B., Fukami, M., Rump, A., Niesler, B., Mertz, A., Muroya, K., Binder, G., Kirsch, S., Winkelmann, M., Nordsiek, G., Heinrich, U., Breuning, M. H., Ranke, M. B., Rosenthal, A., Ogata, T., Rappold, G. A. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nature Genet. 16: 54-63, 1997. [PubMed: 9140395] [Full Text: https://doi.org/10.1038/ng0597-54]
Rappold, G. A., Fukami, M., Niesler, B., Schiller, S., Zumkeller, W., Bettendorf, M., Heinrich, U., Vlachopapadoupoulou, E., Reinehr, T., Onigata, K., Ogata, T. Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature. J. Clin. Endocr. Metab. 87: 1402-1406, 2002. [PubMed: 11889216] [Full Text: https://doi.org/10.1210/jcem.87.3.8328]
Rappold, G., Blum, W. F., Shavrikova, E. P., Crowe, B. J., Roeth, R., Quigley, C. A., Ross, J. L., Niesler, B. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J. Med. Genet. 44: 306-313, 2007. [PubMed: 17182655] [Full Text: https://doi.org/10.1136/jmg.2006.046581]
Ross, J. L., Scott, C., Jr., Marttila, P., Kowal, K., Nass, A., Papenhausen, P., Abboudi, J., Osterman, L., Kushner, H., Carter, P., Ezaki, M., Elder, F., Wei, F., Chen, H., Zinn, A. R. Phenotypes associated with SHOX deficiency. J. Clin. Endocr. Metab. 86: 5674-5680, 2001. [PubMed: 11739418] [Full Text: https://doi.org/10.1210/jcem.86.12.8125]
Sabherwal, N., Bangs, F., Roth, R., Weiss, B., Jantz, K., Tiecke, E., Hinkel, G. K., Spaich, C., Hauffa, B. P., van der Kamp, H., Kapeller, J., Tickle, C., Rappold, G. Long-range conserved non-coding SHOX sequences regulate expression in developing chicken limb and are associated with short stature phenotypes in human patients. Hum. Molec. Genet. 16: 210-222, 2007. [PubMed: 17200153] [Full Text: https://doi.org/10.1093/hmg/ddl470]
Sabherwal, N., Blaschke, R. J., Marchini, A., Heine-Suner, D., Rosell, J., Ferragut, J., Blum, W. F., Rappold, G. A novel point mutation A170P in the SHOX gene defines impaired nuclear translocation as a molecular cause for Leri-Weill dyschondrosteosis and Langer dysplasia. J. Med. Genet. 41: e83, 2004. Note: Electronic Article. [PubMed: 15173249] [Full Text: https://doi.org/10.1136/jmg.2003.016402]
Sabherwal, N., Schneider, K. U., Blaschke, R. J., Marchini, A., Rappold, G. Impairment of SHOX nuclear localization as a cause for Leri-Weill syndrome. J. Cell Sci. 117: 3041-3048, 2004. [PubMed: 15173321] [Full Text: https://doi.org/10.1242/jcs.01152]
Schiller, S., Spranger, S., Schechinger, B., Fukami, M., Merker, S., Drop, S. L. S., Troger, J., Knoblauch, H., Kunze, J., Seidel, J., Rappold, G. A. Phenotypic variation and genetic heterogeneity in Leri-Weill syndrome. Europ. J. Hum. Genet. 8: 54-62, 2000. [PubMed: 10713888] [Full Text: https://doi.org/10.1038/sj.ejhg.5200402]
Schneider, K. U., Marchini, A., Sabherwal, N., Roth, R., Niesler, B., Marttila, T., Blaschke, R. J., Lawson, M., Dumic, M., Rappold, G. Alteration of DNA binding, dimerization, and nuclear translocation of SHOX homeodomain mutations identified in idiopathic short stature and Leri-Weill dyschondrosteosis. Hum. Mutat. 26: 44-52, 2005. [PubMed: 15931687] [Full Text: https://doi.org/10.1002/humu.20187]
Schneider, K. U., Sabherwal, N., Jantz, K., Roth, R., Muncke, N., Blum, W. F., Cutler, G. B., Jr., Rappold, G. Identification of a major recombination hotspot in patients with short stature and SHOX deficiency. Am. J. Hum. Genet. 77: 89-96, 2005. [PubMed: 15931595] [Full Text: https://doi.org/10.1086/431655]
Shears, D. J., Guillen-Navarro, E., Sempere-Miralles, M., Domingo-Jimenez, R., Scambler, P. J., Winter, R. M. Pseudodominant inheritance of Langer mesomelic dysplasia caused by a SHOX homeobox missense mutation. Am. J. Med. Genet. 110: 153-157, 2002. [PubMed: 12116253] [Full Text: https://doi.org/10.1002/ajmg.10421]
Shears, D. J., Vassal, H. J., Goodman, F. R., Palmer, R. W., Reardon, W., Superti-Furga, A., Scambler, P. J., Winter, R. M. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nature Genet. 19: 70-73, 1998. [PubMed: 9590293] [Full Text: https://doi.org/10.1038/ng0198-70]
Spranger, S., Schiller, S., Jauch, A., Wolff, K., Rauterberg-Ruland, I., Hager, D., Tariverdian, G., Troger, J., Rappold, G. Leri-Weill syndrome as part of a contiguous gene syndrome at Xp22.3. Am. J. Med. Genet. 83: 367-371, 1999. [PubMed: 10232745] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990423)83:5<367::aid-ajmg5>3.0.co;2-k]
Thomas, N. S., Maloney, V., Bass, P., Mulik, V., Wellesley, D., Castle, B. SHOX mutations in a family and a fetus with Langer mesomelic dwarfism. Am. J. Med. Genet. 128A: 179-184, 2004. [PubMed: 15214013] [Full Text: https://doi.org/10.1002/ajmg.a.30095]
Zinn, A. R., Ramos, P., Ross, J. L. A second recombination hotspot associated with SHOX deletions. (Letter) Am. J. Hum. Genet. 78: 523-525, 2006. [PubMed: 16572514] [Full Text: https://doi.org/10.1086/500958]
Zinn, A. R., Wei, F., Zhang, L., Elder, F. F., Scott, C. I., Jr., Marttila, P., Ross, J. L. Complete SHOX deficiency causes Langer mesomelic dysplasia. Am. J. Med. Genet. 110: 158-163, 2002. [PubMed: 12116254] [Full Text: https://doi.org/10.1002/ajmg.10422]
Zuffardi, O., Maraschio, P., Lo Curto, F., Muller, U., Giarola, A., Perotti, L. The role of Yp in sex determination: new evidence from X/Y translocations. Am. J. Med. Genet. 12: 175-184, 1982. [PubMed: 6954848] [Full Text: https://doi.org/10.1002/ajmg.1320120207]