Alternative titles; symbols
HGNC Approved Gene Symbol: RMRP
SNOMEDCT: 7720002;
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:35,657,750-35,658,019 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.3 | Anauxetic dysplasia 1 | 607095 | Autosomal recessive | 3 |
| Cartilage-hair hypoplasia | 250250 | Autosomal recessive | 3 | |
| Metaphyseal dysplasia without hypotrichosis | 250460 | Autosomal recessive | 3 |
Mitochondrial RNA-processing endoribonuclease (RNase MRP) cleaves mitochondrial RNA complementary to the light chain of the displacement loop (D loop) at a unique site (Chang and Clayton, 1987). The enzyme is a ribonucleoprotein whose RNA component is a nuclear gene product. The RNA component is the first known RNA encoded by a single-copy gene in the nucleus and imported into mitochondria. The RMRP gene is untranslated, i.e., it encodes an RNA, not a protein (summary by Hsieh et al., 1990).
Topper and Clayton (1990) cloned human RMRP from a placenta genomic DNA library. The RMRP transcript contains approximately 265 nucleotides but shows some heterogeneity at the 3-prime end. Mouse and human RMRP share approximately 84% identity within the transcribed region, and they are similar as far as 715 bp upstream. Little to no homology exists between them in the downstream region. Northern blot analysis of fractionated mouse and human cells revealed RMRP expression in nucleus and mitochondria. A processed form of human RMRP, representing 108 nucleotides from the 3-prime region, in addition to the 5-prime fragment, was detected in the mitochondrial fraction of human KB cells. A similar cleavage occurred in mouse Rmrp, but was offset by 17 bases compared with the human cleavage site. In both cases, processing occurred at the sequence ANCCCGC.
By sequencing normal human liver RNA, Rogler et al. (2014) identified RNAs of about 20 nucleotides originating from the 5-prime end of the RMRP transcript, which they called RMRPS1, and the middle of the RMRP transcript, which they called RMRPS2. RNA sequencing and Northern blot analysis showed that the ratio of RMRPS1 to RMRPS2 transcripts differed among human cells and tissues, and between normal and disease state. These small RNAs represented only a small fraction of total RMRP. In addition to RMRPS1 and RMRPS2 transcripts, Northern blot analysis revealed numerous larger fragments corresponding to the 5-prime and 3-prime ends of RMRP.
Rogler et al. (2014) determined the secondary structure of RMRP in solution. RMRP could adopt at least 2 alternative structures, and the RMRPS1 and RMRPS2 RNAs originated from distinct stem-loop structures. The authors hypothesized that the 2 conformations of RMRP may differentially promote processing of RMRPS1 and RMRPS2.
By study of interspecific somatic cell hybrids and by in situ hybridization, Hsieh et al. (1989, 1990) located the RMRP gene to 9p21-p12. By interspecific hybrids, the corresponding gene was assigned to mouse chromosome 4.
Using inhibitory complementary oligonucleotides, Topper and Clayton (1990) showed that both the 5-prime and 3-prime ends of human RMRP were required for endonuclease activity by ribonucleoproteins from mitochondrial and nuclear extracts.
Clayton (2001) discussed the probable function of RMRP.
To provide a physiologic demonstration of a function for RNase MRP in mammalian cells, Thiel et al. (2005) performed functional studies in yeast and humans. They showed that different RMRP gene mutations lead to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell cycle regulation. Clinical heterogeneity was explained by a correlation between the level and type of functional impairment in vitro and the severity of short stature or predisposition to cancer. Whereas the cartilage-hair hypoplasia (CHH; 250250) founder 70A-G mutation (157660.0001) affected both pathways intermediately, mutations resulting in anauxetic dysplasia (607095) did not affect B-cyclin (123836) mRNA levels but did severely incapacitate ribosomal assembly via defective endonucleolytic cleavage. Anauxetic dysplasia mutations thus lead to poor processing of ribosomal RNA while allowing normal mRNA processing and, therefore, genetically separate the different functions of RNase MRP.
Maida et al. (2009) demonstrated that TERT (187270) interacts with RMRP, which is mutated in cartilage-hair hypoplasia. Human TERT and RMRP form a distinct ribonucleoprotein complex that has RNA-dependent RNA polymerase activity and produces double-stranded RNAs (dsRNAs) that can be processed into small interfering RNA (siRNA) in a Dicer (606241)-dependent manner. Maida et al. (2009) showed that the human TERT-RMRP RNA-dependent RNA polymerase (RdRP) shows a strong preference for RNA templates that can form 3-prime fold-back structures. Using RMRP as a template, the TERT-RMRP RdRP produces dsRNAs that are processed by Dicer into 22-nucleotide dsRNAs that contain 5-prime monophosphate and 3-prime hydroxyl groups that are loaded into AGO2 (606229), confirming that these short RNAs represent endogenous siRNAs. The involvement of human TERT in 2 syndromes characterized by stem cell failure (cartilage-hair hypoplasia and dyskeratosis congenita, 127550) suggested to Maida et al. (2009) that ribonucleoprotein complexes containing TERT have a critical role in stem cell biology.
Using small interfering RNA, Rogler et al. (2014) found that knockdown of DICER (DICER1; 606241) reduced RMRPS1 and RMRPS2 transcript levels in HEK293 cells. Using mimic and oligonucleotide inhibitors, they found that RMRPS1 and RMRPS2 transcripts had widespread effects on gene regulation, with both predominantly repressing gene expression. Analysis of gene pathways suggested that RMRPS1 was predominantly involved in regulation of connective tissue and osteoblast development and maturation, whereas RMRPS2 was predominantly involved in skeletal and muscle development, hematologic system development, and cancer. Both appeared to regulate genes important in cellular proliferation and that produce components of the U11/U12 spliceosome (e.g., RNU4ATAC; 601428).
Cartilage-Hair Hypoplasia
Using a positional cloning strategy and mutation analysis, Ridanpaa et al. (2001) showed that homozygous or compound heterozygous mutations in the RMRP gene (157660.0001-157660.0008) are responsible for cartilage-hair hypoplasia (CHH; 250250), an autosomal recessive disorder characterized by disproportionate short stature, hypoplastic hair, ligamentous laxity, defective immunity, hypoplastic anemia, and neuronal dysplasia of the intestine. The mutations identified in patients with CHH were of 2 distinct types. The first category consisted of insertions or duplications between 6 and 30 nucleotides long residing in the region between the TATA box and the transcription initiation site. These mutations interfered with the transcription of the RMRP gene. The second category consisted of single-nucleotide substitutions and other changes involving at most 2 nucleotides. These resided in highly conserved residues of the transcribed sequence.
Ridanpaa et al. (2002) described 36 different mutations in the RMRP gene in 91 Finnish and 44 non-Finnish CHH families. Based on their nature and localization, these mutations could be classified into 3 categories: mutations affecting the promoter region, small changes of conserved nucleotides in the transcript, and insertions and duplications in the 5-prime end of the transcript. The only region of known function that seemed to avoid mutations was the nucleolar localization signal region between nucleotides 23 and 62. Eight different mutations in the promoter region and 28 mutations in the RNA coding region of 267 nucleotides were reported. The most common mutation in CHH patients was the 70A-G transition (157600.0001). This mutation represented 92% of the mutations in Finnish CHH patients. Studies of linkage disequilibrium based on maximum likelihood estimates with close markers, genealogic studies, and haplotype data suggested that the mutation was introduced to Finland some 3,900 to 4,800 years ago and before the expansion of the population. The same major mutation accounted for 48% of the mutations among CHH patients from other parts of Europe, North and South America, the Near East, and Australia. In the non-Finnish CHH families, the 70A-G mutation segregated with the same major haplotype, although shorter, as in most of the Finnish families. In 23 of these 27 chromosomes, the common region extended over 60 kb; therefore, all the chromosomes most likely arose from a solitary event many thousands of years ago.
Among the sporadic cases of CHH in which Ridanpaa et al. (2002) identified mutations in the RMRP gene were 1 from China, 2 from Israel, and 1 from Turkey. Families with more than 1 affected member affected by CHH and found to have RMRP mutations were from Saudi Arabia and Poland.
Nakashima et al. (2003) identified novel mutations in the RMRP gene in Japanese patients, but did not find the 70A-G common founder mutation in any of the 12 patients studied.
Kuijpers et al. (2003) described a female patient in whom the diagnosis of kyphomelic dysplasia (211350) was made in infancy because of her short-limb dwarfism and kyphomelia, especially of the femurs. She developed a combined aplastic anemia and immunodeficiency by the age of 2 years. These responded well to allogeneic bone marrow transplantation from her HLA-identical brother at the age of 3 years. Growth remained extremely retarded, however. Clinical and radiologic features reported up to the age of 8 years gradually changed and became more typical for CHH, as was confirmed by the finding of compound heterozygosity for 2 novel mutations in the RMRP gene: 195insT (157660.0016) and 63C-T (157660.0017). The 63C-T mutation was said to have previously been found in an Australian CHH patient. Both mutations resided in evolutionarily conserved nucleotides and were not found in healthy controls. Molecular studies in the parents showed the father to have the 195insT and the mother to have the 63C-T mutation.
Hermanns et al. (2005) studied the effects of mutations in both the promoter and the transcribed region of RMRP. While mutations in the promoter abolished transcription in vitro, RMRP RNA levels in patients with transcribed mutations were also decreased, suggesting an unstable RNA. RMRP mutations introduced into the yeast ortholog nuclear mitochondrial endonuclease-1 (Nme1) exhibited normal mitochondrial function, chromosomal segregation, and cell cycle progression, while a CHH fibroblast cell line exhibited normal mitochondrial content. However, the most commonly found mutation in CHH patients, 70A-G (157660.0001), caused an alteration in ribosomal processing by altering the ratio of the short versus the long form of the 5.8S rRNA in yeast. Transcriptional profiling of CHH patient RNAs showed upregulation of several cytokines and cell cycle regulatory genes, 1 of which has been implicated in chondrocyte hypertrophy. Hermanns et al. (2005) suggested that alteration of ribosomal processing in CHH may be associated with altered cytokine signaling and cell cycle progression in terminally differentiating cells in the lymphocytic and chondrocytic cell lineages.
Hirose et al. (2006) screened 9 Japanese patients for mutations in the RMRP gene and identified homozygous or compound heterozygous mutations in 6 patients. The authors noted that the 70A-G founder mutation prevalent in Western populations had not been found in Japanese patients, whereas 2 mutations common in Japanese patients, 218A-G (157660.0013) and a 17-bp duplication at nucleotide 3 (157660.0014), had not been reported in other populations. Haplotype analysis revealed that the 2 latter mutations were contained within rare distinct haplotypes, indicating the presence of unique founders among Japanese CHH patients. Hirose et al. (2006) observed that none of the Japanese patients they evaluated exhibited all of the skeletal, hair, and immunologic features characteristic of classic CHH.
In 27 CHH patients referred for molecular evaluation of the clinical diagnosis, Hermanns et al. (2006) found RMRP mutations in 22. The phenotype in 1 of the 5 mutation-negative patients was fully congruent with the adopted case definition of CHH. In a second of these patients, the diagnosis of Schmid type metaphyseal chondrodysplasia (156500) was made and confirmed by the detection of a mutation in the COL10A1 gene. The remaining patients most likely represented one or more metaphyseal chondrodysplasias not hitherto delineated. The pattern of cumulative growth in infancy and early childhood in the latter 4 patients was the single feature with greatest negative predictive power for CHH. Fourteen of the mutations reported by Hermanns et al. (2006) had not been reported previously. Only 4 of 22 CHH patients were homozygous for the 70A-G mutation. Ridanpaa et al. (2002) postulated that the 70A-G mutation was of ancient founder origin.
Nakashima et al. (2007) performed RT-PCR analysis of cDNA from CHH patients carrying RMRP mutations, including 2 promoter mutations, a 16-bp duplication at +1 and a 17-bp duplication at +3 (157660.0014), and 2 transcribed mutations, 168G-A and 218A-G (157660.0013), and confirmed lower expression levels of RMRP for all mutations. By 5-prime RACE analysis, they showed that reduced transcription in the promoter mutants was accompanied by shifting of the transcription initiation sites to nucleotides 5-prime upstream of the authentic site. By RT-PCR analysis of mouse fibroblasts transfected with transcribed mutant RMRP, they confirmed reduced RMRP expression. Reduced transcription correlated with greater instability of mutant RMRP transcripts compared to controls. A comparable reduction of transcription was seen when the major CHH mutation 70A-G was introduced into mouse ES cells, and low expression level of the 70A-G Rmrp RNA was confirmed by expression assays in cultured cells, and again correlated with RNA instability. Nakashima et al. (2007) concluded that loss of mutant RNA transcripts is a critical feature of pathogenesis of CHH.
In a Finnish girl with CHH who had normal height in childhood, Klemetti et al. (2017) identified compound heterozygosity for mutations in the RMRP gene: the 70A-G mutation and a 10-bp duplication (157660.0003). Her parents were each heterozygous for one of the mutations. Klemetti et al. (2017) identified 3 additional Finnish patients with this genotype, 2 of whom had unusually mild growth failure. Despite their mild growth retardation, the patients had evidence of significant immunodeficiency.
Metaphyseal Dysplasia without Hypotrichosis
Bonafe et al. (2002) identified compound heterozygous mutations in the RMRP gene (157660.0001; 157660.0009-157660.0011) in 2 unrelated patients with metaphyseal dysplasia without hypotrichosis (MDWH; 250460) and concluded that the disorder is a variant of CHH, manifesting only as short stature and metaphyseal dysplasia. Sequencing 120 RMRP alleles from a control group, Bonafe et al. (2002) found an unusually high density of single-nucleotide polymorphisms (SNPs) in and around the RMRP gene. The biologic significance of this finding was unclear.
Ridanpaa et al. (2003) studied the RMRP gene and the H1RNA gene (608513) in 20 patients with the diagnosis of Schmid-type metaphyseal chondrodysplasia (156500) in whom no mutations were detectable in the COL10A1 gene (120110). Two patients were found to be homozygous for a 70A-G transition in the RMRP gene, which is the major mutation causing CHH. The description suggests the metaphyseal dysplasia without hypotrichosis described by Bonafe et al. (2002).
Among 10 Finnish patients with MDWH, Vakkilainen et al. (2020) found that 7 were homozygous for the 71A-G founder mutation (157660.0001) and 3 were compound heterozygous for the founder mutation with 263G-T (157660.0002). No evidence of genotype-phenotype correlation was seen.
In a Finnish patient with MDWH, Vakkilainen et al. (2020) identified compound heterozygosity for variants in the RMRP gene, 155G-T (157660.0023) and -5delins21 (157660.0024).
Anauxetic Dysplasia
Thiel et al. (2005) performed positional cloning at the locus for anauxetic dysplasia (ANXD; 607095), a rare autosomal recessive spondylometaepiphyseal dysplasia characterized by the prenatal onset of extreme short stature, an adult height of less than 85 cm, hypodontia, and mild mental retardation. Homozygosity mapping led to the identification of novel mutations in the RMRP gene (157660.0018-157660.0021), indicating that the disorder is allelic to cartilage-hair hypoplasia (250250) as well as to metaphyseal dysplasia without hypotrichosis.
Thiel et al. (2007) stated that in addition to the founder mutation 70A-G, which is present in 92% of Finnish and 48% of non-Finnish patients with CHH, a total of 25 insertions or duplications between the TATA box and the transcription start site and more than 62 other mutations within the RMRP gene had been identified in patients with phenotypes in the cartilage hair hypoplasia-anauxetic dysplasia (CHH-ANXD) spectrum. That spectrum, ranging from the milder phenotypes metaphyseal dysplasia without hypotrichosis (MDWH; 250460) and CHH to the severe anauxetic dysplasia, includes different degrees of short stature, hair hypoplasia, defective erythrogenesis, and immunodeficiency. To investigate the genotype-phenotype correlation, Thiel et al. (2007) analyzed the position and the functional effect of 13 mutations in patients with variable features of the CHH-ANXD spectrum. Those at the severe end of the spectrum included a patient with anauxetic dysplasia who was compound heterozygous for a null deletion mutation (157660.0022) and the 195C-T mutation (see 157660.0009), which had been described in patients with milder phenotypes. Mapping of nucleotide conservation to the 2-dimensional structure of the RMRP transcript showed that disease-causing mutations either affect evolutionarily conserved nucleotides or are likely to alter secondary structure through mispairing in stem regions. In vitro testing of mitochondrial RNA-processing ribonuclease multiprotein-specific mRNA and rRNA cleavage of different mutations showed a strong correlation between the decrease in rRNA cleavage in ribosomal assembly and the degree of bone dysplasia, whereas reduced mRNA cleavage, and thus cell cycle impairment, predicted the presence of hair hypoplasia, immunodeficiency, and hematologic abnormalities and thus increased cancer risk.
The article by Huang et al. (2015) identifying Ddx5 as an Ror-gamma-t (see 602943)-interacting protein in mouse T-helper-17 (Th17) cells (see IL17A, 603149) and concluding that gly270 in Rmrp was critical for Ddx5-Ror-gamma-t complex assembly and for recruitment of Rmrp to Ror-gamma-t loci to coordinate the Th17 effector program was retracted because key aspects of the original results could not be replicated.
Cartilage-Hair Hypoplasia
Ridanpaa et al. (2001) identified homozygosity for an A-to-G transition at nucleotide 70 (70A-G) of the RMRP gene in 42 Finnish families with cartilage-hair hypoplasia (CHH; 250250), including 12 with more than 1 affected child and 30 with a single affected child. All of these families carried modifications of the ancestral haplotype of DNA polymorphisms. In additional CHH patients, the authors identified the 70A-G mutation in compound heterozygosity with another RMRP mutation (e.g., 157660.0002). Another patient, who had been described as patient A by Sulisalo et al. (1997), had uniparental disomy for chromosome 9 with 2 copies of the maternal, 70A-G mutation-carrying chromosome, and no paternal chromosome 9. The 70A-G mutation was detected in heterozygosity in 1 of 120 Finnish control samples and in 2 of 160 non-Finnish control samples.
Ridanpaa et al. (2003) reported that the most frequent, and perhaps only, mutation causing CHH in the Old Order Amish in the United States (in whom the disorder was first described) is the same 70A-G transition that is the major mutation causing CHH in Finns. They stated that although more than 40 different mutations in the RMRP gene had been characterized in other populations, 70A-G was the most common CHH-causing mutation worldwide. The mutation segregates with the same major haplotype in Finns and Amish and others, suggesting that it is very ancient.
Ridanpaa et al. (2003) found homozygosity for the common Finnish mutation in 2 of 20 Canadian patients diagnosed with Schmid-type metaphyseal chondrodysplasia (156500) without the usual autosomal dominant mutation in COL10A1 (120110). The patients later developed features more typical of CHH.
Hermanns et al. (2006) found the 70A-G mutation in patient number 1 of Williams et al. (2005) with CHH complicated by severe macrocytic anemia. Repeated transfusions with irradiated packed red blood cells were required. The patient remained transfusion-dependent but showed no signs of compromised immunity. The usually mild anemia of CHH is most probably self-limited. However, over half of CHH patients with severe anemia may require life-long transfusions and bone marrow transplantation (Williams et al., 2005).
The so-called Finnish-Amish common transition 70A-G was observed in 12 alleles among 22 confirmed CHH patients (27%) by Hermanns et al. (2006).
Klemetti et al. (2017) identified 4 Finnish patients with CHH who were compound heterozygous for the 70A-G mutation and a 10-bp duplication at posistion -13 (TACTCTGTGA) (157660.0003) in the RMRP gene. Three of the 4 had unusually mild growth failure, but evidence of significant immunodeficiency.
Metaphyseal Dysplasia without Hypotrichosis
In an Austrian boy with metaphyseal chondrodysplasia without hypotrichosis (MDWH; 250460), Bonafe et al. (2002) identified compound heterozygosity for mutations in the RMRP gene: the common Finnish 70A-G mutation and a 238C-T transition (157660.0009).
In 6 Finnish families with cartilage-hair hypoplasia (CHH; 250250), including 1 family with 2 affected children, Ridanpaa et al. (2001) identified a G-to-T transversion at nucleotide 262 (262G-T) of the RMRP gene in compound heterozygosity with the 70A-G mutation (157660.0001). The chromosomes carrying the 262G-T mutation shared a haplotype that differed from that of the main ancestral one. The 262G-T mutation was not detected in any of 120 Finnish and 160 non-Finnish controls.
Ridanpaa et al. (2001) identified a 10-bp duplication (TACTCTGTGA) at position -13 of the RMRP gene in compound heterozygosity with the 70A-G mutation (157660.0001) in 2 Finnish families with cartilage-hair hypoplasia (CHH; 250250). The chromosomes carrying this mutation shared a haplotype that differed from the ancestral one. This and all other duplication-insertions found in the RMRP gene were not detected in 120 Finnish and 160 non-Finnish controls.
Klemetti et al. (2017) identified 4 Finnish patients with CHH who were compound heterozygous for the 10-bp duplication at position -13 and the 70A-G mutation in the RMRP gene. Three of the 4 had unusually mild growth failure but evidence of significant immunodeficiency.
In a Swiss patient with cartilage-hair hypoplasia (CHH; 250250), Ridanpaa et al. (2001) identified a 15-bp duplication (ACTACTCTGTGAAGC) that occurred twice at position -10 of the RMRP gene in compound heterozygosity with a 2-bp duplication at nucleotide 98 (157660.0005).
Ridanpaa et al. (2001) identified a 2-bp duplication (TG) at nucleotide 98 of the RMRP gene in compound heterozygosity with a 15-bp duplication at position -10 (157660.0004) in a Swiss patient with cartilage-hair hypoplasia (250250) and with the 70A-G mutation (157660.0001) in a Canadian patient with CHH.
Ridanpaa et al. (2001) identified a 6-bp insertion (CCTGAG) at position -6 of the RMRP gene in compound heterozygosity with the 70A-G mutation (157660.0001) in a German patient with cartilage-hair hypoplasia (CHH; 250250).
In an English patient with cartilage-hair hypoplasia (CHH; 250250), Ridanpaa et al. (2001) identified an 18-bp duplication (TCTGTGAAGCTGAGGAC) at position -3 of the RMRP gene in compound heterozygosity with a G-to-A transition at nucleotide 193 (193G-A; 157660.0008). The 193G-A mutation was not found in 112 Finnish and 93 non-Finnish controls.
For discussion of the 193G-A transition in the RMRP gene that was found in a patient with cartilage-hair hypoplasia (CHH; 250250) by Ridanpaa et al. (2001), see 157660.0007.
In an Austrian boy with short stature and metaphyseal dysplasia similar to CHH, but lacking hair anomalies, immunodeficiency, and other extraskeletal features (MDWH; 250460), Bonafe et al. (2002) identified compound heterozygous mutations in the RMRP gene: the common Finnish 70A-G mutation (157660.0001) and a 238C-T transition.
In a boy of Swiss-Danish extraction with short stature and metaphyseal dysplasia similar to CHH, but lacking hair anomalies, immunodeficiency, and other extraskeletal features (MDWH; 250460), Bonafe et al. (2002) identified compound heterozygous mutations in the RMRP gene: a 195C-T transition and a 12-bp duplication (AAGCTGAGGACG) located 2 nucleotides before the transcription initiation site (157660.0011).
For discussion of the 12-bp duplication in the RMRP gene that was found in compound heterozygous state in patients with metaphyseal dysplasia without hypotrichosis (MDWH; 250460) by Bonafe et al. (2002), see 157660.0010.
Nakashima et al. (2003) described a 7-year-old Japanese girl who had skeletal changes consistent with cartilage-hair hypoplasia but who showed neither hypoplastic hair nor immunodeficiency (MDWH; 250460). Radiography showed brachydactyly with cone-shaped epiphyses in the phalanges of the hands and metaphyseal dysplasia in the long and short tubular bones, especially in the distal femur. Mutation analysis showed compound heterozygosity for mutations in the RMRP gene: a 17-bp insertion (TCTGTGAAGCTGGGGAC) at -20 and a 218A-G transition (157660.0013). The insertion was found on the paternal allele and the nucleotide substitution on the maternal allele.
For discussion of the 218A-G transition in the RMRP gene that was found in compound heterozygous state in a patient with metaphyseal dysplasia without hypotrichosis (MDWH; 250460) by Nakashima et al. (2003), see 157660.0012.
In a Japanese patient with cartilage-hair hypoplasia (CHH; 250250), Nakashima et al. (2003) identified compound heterozygosity for 2 mutations in the RMRP gene: a 17-bp duplication (GAAGCTGAGGACGTGGT) at +3 inherited from the mother and a de novo 182G-A mutation (157660.0015). Parenthood was confirmed by testing for polymorphic markers.
For discussion of the de novo 182G-A mutation in the RMRP gene that was found in compound heterozygous state in a patient with cartilage-hair hypoplasia (CHH; 250250) by Nakashima et al. (2003), see 157660.0014. Nakashima et al. (2003) stated that the 182G-A mutation was the first de novo mutation in the RMRP gene to be reported.
Kuijpers et al. (2003) described a girl who in the first 2 years of life was thought to have kyphomelic dysplasia (211350) because of her short-limb dwarfism and bowed extremities affecting especially the femurs. At the age of 2 years she developed a combined immunodeficiency and aplastic anemia that responded well to allogeneic bone marrow transplantation, although growth remained extremely retarded. Over 8 years of observation, clinical and radiologic symptoms gradually changed and became more typical for CHH (250250). Compound heterozygosity for 2 novel mutations in the RMRP gene were found: 195insT and 63C-T (157660.0013).
For discussion of the 63C-T transition in the RMRP gene that was found in compound heterozygous state in a patient with cartilage-hair hypoplasia (CHH; 250250) by Kuijpers et al. (2003), see 157660.0016.
In 3 affected members of a Jordanian family with anauxetic dysplasia (ANXD1; 607095) reported by Menger et al. (1996), Thiel et al. (2005) found homozygosity for an insertion of 14 nucleotides between nucleotides 111 and 112 of the RMRP cDNA. The parents were consanguineous.
In the German family with anauxetic dysplasia (ANXD1; 607095) reported by Horn et al. (2001), Thiel et al. (2005) found that both affected members were compound heterozygous for 2 mutations of the RMRP gene: 14G-A and 90_91AG-GC (157660.0020).
In a family with 2 affected children with anauxetic dysplasia (ANXD1; 607095) reported by Horn et al. (2001) and in a single patient (patient 3), Thiel et al. (2005) found the same mutation in the RMRP gene, 90_91AG-GC. The family and the single patient were from the same region of Germany and carried the 90_91AG-GC mutation on the same ancestral haplotype, confirming a founder effect. The mutation occurred in compound heterozygosity in all 3 individuals, with a 14G-A mutation in the family (157660.0019) and with a 254C-G mutation in the single patient (157660.0021).
Thiel et al. (2005) found an individual (patient 3) with anauxetic dysplasia (ANXD1; 607095), the offspring of nonconsanguineous parents, to be compound heterozygous for 90_91AG-GC (157660.0020) and 254C-G mutations in the RMRP gene.
In a patient with anauxetic dysplasia (ANXD1; 607095), Thiel et al. (2007) found compound heterozygosity for a 10-bp null mutation of the RMRP gene (254_263delCTCAGCGCGG) and the transcribed mutation 195C-T (157660.0009), which had previously been described in patients with milder phenotypes.
In a Finnish patient with metaphyseal dysplasia without hypotrichosis (MDWH; 250460), Vakkilainen et al. (2020) identified compound heterozygosity for mutations in the RMRP gene, a 155G-T transversion (n.155G-T, NR_003051.3) and a deletion/insertion in the promoter (n.-5delins21, 157660.0024). This patient developed severe agranulocytosis at age 18 years and underwent hematopoietic stem cell transplantation (HSCT).
For discussion of the deletion/insertion mutation (n.-5delins21, NR_003051.3) in the RMRP gene that was found in compound heterozygous state in a patient with metaphyseal dysplasia without hypotrichosis (MDWH; 250460) by Vakkilainen et al. (2020), see 157660.0023.
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