Alternative titles; symbols
HGNC Approved Gene Symbol: TWIST1
SNOMEDCT: 83015004;
Cytogenetic location: 7p21.1 Genomic coordinates (GRCh38): 7:19,113,047-19,117,636 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p21.1 | Craniosynostosis 1 | 123100 | Autosomal dominant | 3 |
| Robinow-Sorauf syndrome | 180750 | Autosomal dominant | 3 | |
| Saethre-Chotzen syndrome with or without eyelid anomalies | 101400 | Autosomal dominant | 3 | |
| Sweeney-Cox syndrome | 617746 | Autosomal dominant | 3 |
TWIST1 belongs to the basic helix-loop-helix (bHLH) class of transcriptional regulators that recognize a consensus DNA element called the E box (Pan et al., 2009).
By PCR of a placenta cDNA library using primers based on mouse Twist, Bourgeois et al. (1996) cloned human TWIST. The deduced 206-amino acid protein contains a central DNA-binding basic region followed by a helix-loop-helix domain. Mouse and human TWIST share 96.6% amino acid identity. In vitro-translated TWIST had an apparent molecular mass of 25 kD.
By selecting genes overexpressed in young quiescent human fibroblasts compared with senescent cells, followed by database analysis and screening a genomic library, Wang et al. (1997) cloned TWIST1. The deduced protein contains 201 amino acids and has a calculated molecular mass of 20.9 kD. It has a hydrophilic N terminus, followed by a bHLH DNA-binding and dimerization motif. It also contains several potential phosphorylation sites, including 2 in the loop region of the dimerization domain that are conserved among all species examined. TWIST orthologs were detected in all mammalian species examined, and within mammals, the DNA-binding region showed 100% sequence conservation. A possible ortholog was also detected in chicken, but not in yeast. Northern blot analysis detected a 1.6-kb transcript that was highly expressed in placenta. Lower expression was detected in adult heart and skeletal muscle, and weak expression was found in kidney and pancreas, but not in brain. Expression was detected in endometrial fibroblasts, peritoneal mesothelial cells, and fetal lung fibroblasts, but not in other cell lines examined.
El Ghouzzi et al. (1997) indicated that the TWIST gene contains 2 exons and 1 intron of 538 bp. The single coding exon (exon 1) has 772 bp.
Wang et al. (1997) identified 2 putative TATA boxes within the promoter region of the TWIST1 gene, but only the more proximal TATA box appeared to be functional. They also identified several potential transcription factor-binding sites in the TWIST1 promoter region.
Bourgeois et al. (1996) used isotopic in situ hybridization to map the TWIST1 gene to chromosome 7p21. The murine gene had been mapped to bands B-C1 of chromosome 12 by Mattei et al. (1993).
Studies in Drosophila by Shishido et al. (1993) indicated that Twist may affect the transcription of fibroblast growth factor receptors (FGFRs; see 136350), a gene family implicated in craniosynostosis. The emerging cascade of molecular components involved in craniofacial and limb development included TWIST, which may function as an upstream regulator of FGFRs.
Histone acetyltransferases (HATs) play a critical role in transcriptional control by relieving repressive effects of chromatin (Struhl, 1998). Hamamori et al. (1999) showed that Twist directly binds 2 independent HAT domains of acetyltransferases, p300 (602700) and p300/CBP-associated factor (PCAF; 602303), and directly regulates their HAT activities. The N terminus of Twist is a primary domain interacting with both acetyltransferases, and the same domain is required for inhibition of p300-dependent transcription by Twist. Adenovirus E1A protein mimicked the effects of Twist by inhibiting the HAT activities of p300 and PCAF.
Using electrophoretic mobility shift assays, El Ghouzzi et al. (2001) demonstrated that the TWIST-E12 (TCF3; 147141) dimer specifically recognizes the CATATG motif.
Sosic et al. (2003) showed that Twist and Dermo1 (607556), which they called Twist1 and Twist2, respectively, were induced by a cytokine signaling pathway that required the dorsal-related protein Rela (164014), a member of the nuclear factor kappa-B (NFKB; see 164011) family of transcription factors, in mice. Twist1 and Twist2 repressed cytokine gene expression through interaction with Rela. Mice homozygous for a Twist2 null allele or doubly heterozygous for Twist1 and Twist2 alleles showed elevated expression of proinflammatory cytokines, resulting in perinatal death from cachexia. Sosic et al. (2003) concluded that there is an evolutionarily conserved signaling circuit in which TWIST proteins regulate cytokine signaling by establishing a negative feedback loop that represses the NFKB-dependent cytokine pathway.
Bialek et al. (2004) determined that the Twist proteins transiently inhibit Runx2 (600211) function during skeletal development in mice. Twist1 and Twist2 were expressed in Runx2-expressing cells throughout the skeleton early during development, and osteoblast-specific gene expression occurred only after their expression decreased. Double heterozygotes for Twist1 and Runx2 deletion showed none of the skull abnormalities observed in Runx2 +/- mice, a Twist2 null background rescued the clavicle phenotype of Runx2 +/- mice, and Twist1 or Twist2 deficiency led to premature osteoblast differentiation. The antiosteogenic function of the Twist proteins was mediated by a domain Bialek et al. (2004) called the Twist box, which interacted with the Runx2 DNA-binding domain to inhibit its function.
Using a murine breast tumor model, Yang et al. (2004) determined that Twist plays an essential role in metastasis. Suppression of Twist expression in highly metastatic mammary carcinoma cells specifically inhibited their ability to metastasize from the mammary gland to the lung. Ectopic expression of Twist resulted in loss of E-cadherin (192090)-mediated cell-cell adhesion, activation of mesenchymal markers, and induction of cell motility, suggesting that Twist contributes to metastasis by promoting an epithelial-mesenchymal transition. In human breast cancers, high Twist expression correlated with invasive lobular carcinoma, a highly infiltrating tumor type associated with loss of E-cadherin expression.
Firulli et al. (2005) investigated the biochemical and genetic interactions between Twist1 and Hand2 (602407) both in vitro and during limb development in the chick and mouse. They showed that ectopic expression of the related basic helix-loop-helix factor Hand2 phenocopies Twist1 loss of function in the limb and that the 2 factors have a gene dosage-dependent antagonistic interaction. Dimerization partner choice by Twist1 and Hand2 can be modulated by protein kinase A (see 176911)- and protein phosphatase 2A (see 176915)-regulated phosphorylation of conserved helix I residues.
Stasinopoulos et al. (2005) found that HOXA5 (142952) bound TWIST. Using a p53 (TP53; 191170) promoter reporter system in a human TWIST-expressing breast carcinoma cell line, they found that TWIST suppressed p53 activity and that HOXA5 coexpression largely reversed this suppression. TWIST overexpression altered p53 phosphorylation and cell cycle progression in response to radiation. These effects were partially reversed by TWIST-specific small interfering RNA.
Connerney et al. (2006) showed that the activity of TWIST1 in human and mouse cell lines was dependent on its dimer partner. TWIST1 formed both homodimers (T/T) and heterodimers with E2A E proteins (T/E), and the relative level of TWIST1 to the HLH inhibitor Id proteins (see ID1; 600349) determined which dimer formed. On the basis of expression patterns of Twist1 and Id1 within mouse cranial sutures, Connerney et al. (2006) hypothesized that Twist1 forms T/T homodimers in osteogenic fronts and T/E heterodimers in midsutures. In support of this hypothesis, they found that genes regulated by T/T homodimers, such as Fgfr2 and periostin (POSTN; 608777), were expressed in osteogenic fronts, whereas genes regulated by T/E heterodimers, such as thrombospondin-1 (THBS1; 188060), were expressed in the midsutures. The ratio between T/T homodimers and T/E heterodimers was altered in the sutures of Twist1 +/- mice, favoring an increase in homodimers and an expansion of osteogenic fronts. In addition, the T/T to T/E ratio was greater in coronal versus sagittal sutures, which the authors suggested may contribute to making the coronal suture more susceptible to fusion due to Twist1 haploinsufficiency. Connerney et al. (2006) inhibited suture fusion in Twist1 +/- mice by increasing T/E formation either by increasing expression of E12 or by decreasing Id expression. They concluded that dimer partner selection is a critical regulator of TWIST function.
Using quantitative PCR and Northern blot analysis, Pan et al. (2009) found that mouse Twist1 was highly expressed in brown and white fat compared with all other tissues examined. Expression of Twist1 was increased in mature cultured mouse white fat adipocytes compared with preadipocytes, but overexpression of Twist1 did not affect adipogenic differentiation. Twist1 bound Pgc1-alpha (PPARGC1A; 604517) and inhibited its transcriptional activity, leading to reduced Pgc1-alpha-stimulated oxygen consumption and fatty acid oxidation. Binding of Twist1 did not alter Pgc1-alpha localization on target promoters, but it stabilized Pgc1-alpha against ubiquitination and inhibited acetylation of Pgc1-alpha target genes. Stable knockdown of Twist1 via RNA interference in newborn mouse brown fat preadipocytes and in differentiated brown fat cells increased expression of Pgc1-alpha target genes and mitochondrial biogenesis. Conversely, overexpression of Twist1 suppressed expression of Pgc1-alpha target genes, mitochondrial biogenesis, and brown fat metabolism. Agonist-induced Ppar-delta (PPARD; 600409) bound the promoter region of Twist1 and upregulated Twist1 expression in brown fat. Pan et al. (2009) concluded that TWIST1 is involved in a negative feedback regulatory loop with PGC1-alpha and PPAR-delta to modulate brown fat metabolism.
Niesner et al. (2008) showed that Twist1 was transiently expressed in repeatedly activated mouse T helper-1 (Th1) effector memory cells, but not in Th2 or Th17 cells. Th1 cells isolated from chronically inflamed gut tissue of patients with ulcerative colitis or Crohn disease (IBD1; 266600) and joints of patients with spondyloarthropathies (see 106300) or rheumatoid arthritis (180300) expressed high levels of TWIST1, suggesting repeated restimulation and an involvement in disease pathogenesis.
Yang et al. (2012) found that TWIST physically interacts in vivo with the histone lysine methyltransferase SET8 (607240), and that the N-terminal region of SET8 is required for this interaction. TWIST and SET8 cooperated to promote epithelial-mesenchymal transition and metastasis in breast cancer cells following implantation in mice. In knockdown and overexpression studies, TWIST recruited SET8 to the promoter regions of E-cadherin (CDH1; 192090) and N-cadherin (CDH2; 114020), and histone H4 (see 602822) lys20 monomethylation by SET8 resulted in downregulation of E-cadherin and upregulation of N-cadherin.
By a computational approach, Hirsch et al. (2018) identified 12 putative enhancers for the mouse Twist1 gene, located in the neighboring gene Hdac9 and likely regulating Twist1 transcription during limb and brachial arch development. Subsequently, analysis with zebrafish and mice confirmed that 8 of these candidates likely regulated Twist1 fin/limb and branchial expression during embryonic development, and defined the minimal sequences for some of the enhancers required for tissue-specific expression of Twist1. Analysis with 3 enhancers revealed that the Twist1 promoter region interacted with the Twist1 enhancers in the limb bud and branchial arch of mouse embryos, and transcription factors Lmx1b (602575) and Tfap2 (107580) regulated the activity of those enhancers by binding to them. Deletion of some of the enhancers reduced limb bud expression of Twist1 in mice in vivo, and mimicked the preaxial-polydactyly (PPD) phenotype previously observed in a Twist1 +/- mouse model.
Using RT-PCR and Western blot analyses, Vonhogen et al. (2020) found that increased Mir337-3p (620408) expression paralleled decreased Twist1 expression in mouse brown adipose tissue compared with white adipose tissue. Overexpression of Mir337-3p in brown preadipocytes led to reduced Twist1 expression, accompanied by increased expression of brown/mitochondrial markers. Luciferase assays revealed that Mir337-3p targeted Twist1 by interacting with its 3-prime UTR. The authors confirmed the inverse relationship between MIR337-3p and TWIST1 expression in adipose tissue from humans with and without metabolic syndrome (see 605552) and observed dysregulation of the MIR337-3p-TWIST1 axis in metabolic syndrome.
Krebs et al. (1997) found that the breakpoint of an apparently balanced translocation t(6;7)(q16.2;p15.3) associated with a mild form of Saethre-Chotzen syndrome (Tsuji et al., 1995) occurred approximately 5 kb 3-prime of the TWIST locus and deleted 518 bp of chromosome 7. Potential exon sequences flanking the chromosome 7 translocation breakpoint did not hit known genes in database searches. They stated that the chromosome rearrangement downstream of TWIST is compatible with the notion that TWIST is the Saethre-Chotzen syndrome gene and implies loss of function of 1 allele by a positional effect as a possible mechanism of mutation evoking the syndrome.
Saethre-Chotzen Syndrome
Twist is required in head mesenchyme for cranial neural tube morphogenesis in mice. While homozygous Twist-null murine embryos exhibit failure of neural tube closure, heterozygosity for Twist-null mutations results in a moderate phenotype including minor skull and limb anomalies consistent with those of the Saethre-Chotzen syndrome (SCS; 101400). Furthermore, the clinical phenotype of SCS was mapped to 7p22-p21 by linkage analysis; Bourgeois et al. (1996) and Howard et al. (1997) mapped the human TWIST gene to the same region of 7p. This prompted Howard et al. (1997) and El Ghouzzi et al. (1997) to seek mutations in the TWIST gene in SCS. Both groups found a number of mutations occurring within the basic DNA binding, helix I, and loop domains resulting in substitutions or premature termination of the protein.
Rose et al. (1997) reported that the breakpoints in 4 translocation patients with SCS did not interrupt the coding sequence of the TWIST gene and thus most likely were acting through a positional effect. TWIST mutations were found in 12 SCS cases. Four of these families had been used as part of the linkage study of the SCS locus. The mutations detected included missense and nonsense mutations and 3 cases of a 21-bp duplication (601622.0007). Although phenotypically diagnosed as having SCS, 3 families were found to have a pro250-to-arg mutation of FGFR3 (134934.0014).
Wilkie (1997) reviewed genes and mechanisms involved in craniosynostosis. Mutations of 5 genes had yielded new insight into both normal and abnormal cranial suture biogenesis: MSX2 (123101), FGFR1 (136350), FGFR2 (176943), FGFR3 (134934), and TWIST. Whereas the human MSX2 and FGFR mutations involve gain of function, the TWIST mutations largely involve loss of function (haploinsufficiency). This is supported by the evidence of frequent nonsense mutations in the TWIST gene but not in the MSX2 or FGFR genes. Wilkie (1997) commented that the spectra of mutations observed in the TWIST and FGFR genes are highly nonrandom. Although relatively few mutations have been described in TWIST, 21-bp duplications (with 3 distinct molecular origins) comprised about one-third. The explanation can be accommodated within conventional molecular biology, i.e., a repeat unit with 21-bp periodicity is present in that region of chromosome 7 (El Ghouzzi et al., 1997).
Gripp et al. (1999) described a mutation of the TWIST gene (601622.0008) in a patient with unilateral radial aplasia and bicoronal synostosis, features fitting a narrow definition of Baller-Gerold syndrome (BGS; 218600). Because the TWIST mutation pointed to the diagnosis of SCS (101400), the whole family was investigated. Facial asymmetry, prominent nose, high palate, and hallux valgus observed in the father and older sister were consistent with mild presentation of SCS and these 2 individuals were found also to carry the TWIST mutation.
El Ghouzzi et al. (1999) found TWIST mutations in 16 of 22 unrelated patients with Saethre-Chotzen syndrome. All of these mutations involved the bHLH domain of the protein. Mutant genotypes included frameshift deletions/insertions and nonsense and missense mutations, either truncating or disrupting the bHLH motif of the protein. This observation supported the view that most SCS cases result from loss-of-function mutations at the TWIST locus. In 2 of the 22 cases studied, the recurrent P250R mutation of the FGFR3 gene (134934.0014), presenting mild clinical manifestations of Saethre-Chotzen syndrome, was found. In 4 of the 22 cases, no TWIST or FGFR3 mutation was found. Clinical reexamination of patients carrying TWIST mutations failed to reveal correlations between the mutant genotype and severity of the phenotype. No TWIST mutations were detected in 40 cases of isolated coronal craniosynostosis.
Gripp et al. (2000) tabulated 51 mutations in the TWIST gene observed by others and themselves in patients with Saethre-Chotzen syndrome and in a note added in proof described 2 additional mutations.
El Ghouzzi et al. (2000) studied stability, dimerization capacities, and subcellular distribution of 3 types of TWIST mutant. Nonsense mutations resulted in an unstable truncated protein; missense mutations involving the helical domains led to a complete loss of TWIST heterodimerization with the E12 bHLH protein (147141) in a yeast 2-hybrid system, and dramatically altered the ability of the TWIST protein to localize to the nucleus of COS-transfected cells. In-frame insertion or missense mutations within the loop significantly altered dimer formation but not nuclear location of the protein. The authors concluded that at least 2 distinct mechanisms account for loss of TWIST protein function in SCS patients, namely protein degradation and subcellular mislocalization.
By electrophoretic mobility shift assay, El Ghouzzi et al. (2001) found that mutations affecting conserved residues in the basic domain and the loop-helix II junction of TWIST resulted in loss of DNA-binding activity. These mutations did not affect TWIST mRNA stability or targeting and dimerization of the TWIST protein.
In an extensive review of the genetics of craniofacial development and malformation, Wilkie and Morriss-Kay (2001) provided a useful diagram of the molecular pathways in cranial suture development with a listing of all craniofacial disorders caused by mutations in the corresponding genes. Four proteins were indicated as having strong evidence for existing in the pathway, with successive downstream targets as follows: TWIST--FGFR2--FGFR1--CBFA1 (RUNX2).
Yousfi et al. (2002) demonstrated increased osteoblast and osteocyte apoptosis in coronal sutures from 2 SCS patients with nonsense mutations, including Y103X (601622.0001), that result in the synthesis of bHLH-truncated proteins, and one patient with a missense mutation in the basic domain that abolished Twist DNA binding. Mutant-Twist calvarial cells cultured in low serum conditions showed enhanced DNA fragmentation compared to normal age-matched calvarial cells. Biochemical analysis showed increased activity of initiator caspase-2 (600639) and caspase-8 (601763) and downstream effector caspase-3 (600636), caspase-6 (601532), and caspase-7 (601761) in mutant osteoblasts. Mutant-Twist osteoblasts also showed increased cytochrome c release from the mitochondria. However, the activity of the downstream effector caspase-9 (602234) was not increased due to overexpression of the antagonist protein Hsp70 (see 140550). Detection of differentially expressed genes using cDNA expression array revealed increased Bax (600040) and TNF-alpha (191160) mRNA levels in mutant-Twist cells. Neutralization of TNF overexpression using anti-TNF or anti-TNF receptor 1 antibodies abolished the increased activity of caspases-2, -8, -3, -6, and -7 in mutant-Twist osteoblasts. The authors concluded that Twist haploinsufficiency in SCS promotes osteoblast apoptosis by a TNF-caspase cascade, and that Twist plays an antiapoptotic role in human calvarial osteoblasts.
Guenou et al. (2005) reported that cranial osteoblasts from an SCS patient with the Y103X mutation showed decreased FGFR2 (176943) mRNA levels associated with decreased expression of Runx2 (600211), bone sialoprotein (SPP1; 166490) and osteocalcin (BGLAP; 112260), compared to wildtype osteoblasts. Transfection with Twist or Runx2 expression vectors, but not with a Runx2 mutant that impairs DNA binding, restored Fgfr2, Runx2, SPP1 and osteocalcin expression in Twist-mutant osteoblasts. EMSA analysis of mutant osteoblast nuclear extracts showed reduced Runx2 binding to a target OSE2 site in the Fgfr2 promoter. ChIP analyses showed that both Twist and Runx2 in mutant osteoblast nuclear extracts bound to a specific region in the Fgfr2 promoter. Significantly, forced expression of Fgfr2 restored Runx2 and osteoblast marker genes, whereas a dominant-negative Fgfr2 further decreased Runx2 and downstream genes in Twist mutant osteoblasts, indicating that alteration of Fgfr2 resulted in downregulation of osteoblast genes in Twist-mutant osteoblasts. Guenou et al. (2005) concluded that Twist haploinsufficiency downregulates Fgfr2 mRNA expression, which in turn reduces Runx2 and downstream osteoblast-specific genes in human calvarial osteoblasts.
Cai et al. (2003) found by real-time gene dosage analysis that of 55 patients with features of Saethre-Chotzen syndrome, 11% had deletions of the TWIST gene. Two patients had a translocation or inversion at least 260 kb 3-prime of the TWIST gene, suggesting the presence of position-effect mutations. Of the 37 patients with classic features of Saethre-Chotzen syndrome, the overall detection rate for TWIST mutations was 68%. The risk for developmental delay in patients with deletions involving the TWIST gene was approximately 90%, or 8 times, more common than in patients with intragenic mutations.
Firulli et al. (2005) noted that multiple TWIST1 mutations associated with Saethre-Chotzen syndrome alter protein kinase A-mediated phosphorylation of TWIST1, suggesting that misregulation of TWIST1 dimerization through either stoichiometric or posttranslational mechanisms underlies phenotypes of individuals with Saethre-Chotzen syndrome.
Kress et al. (2006) identified 25 mutations in the TWIST1 gene in 71 patients from 39 of 124 pedigrees with coronal suture synostosis. Fourteen novel mutations were identified. Sixty-two of the patients presented with typical features of SCS, whereas 9 were cases of very mild expression that had not been appreciated through inspection alone, and 3 were found only through pedigree analysis.
Robinow-Sorauf Syndrome
In a mother and son with Robinow-Sorauf syndrome (180750), Kunz et al. (1999) identified heterozygosity for a 1-bp insertion in the TWIST1 gene (601622.0009). The authors considered this mutation to be confirmation that the Saethre-Chotzen and Robinow-Sorauf syndromes are at least allelic, if not part of a clinical spectrum of the same condition. Cai et al. (2003) suggested that the diagnosis of Robinow-Sorauf syndrome in the family reported by Kunz et al. (1999) could be questioned because the affected individuals lacked certain characteristics, such as syndactyly, that were found repeatedly in all members of the original Robinow-Sorauf pedigree.
Cai et al. (2003) restudied the original family reported by Robinow and Sorauf (1975) and identified heterozygosity for a truncating mutation in the TWIST gene (Q71X; 601622.0012). Cai et al. (2003) stated that they examined 3 of the 11 affected members of the original family with Robinow-Sorauf syndrome in addition to the propositus and found that all had second interdigital syndactyly as well as a toe deformity (either polydactyly or hallux valgus).
Craniosynostosis 1
Seto et al. (2007) performed mutation analysis in 164 infants with isolated single-suture craniosynostosis (CRS1; 123100) for mutations in TWIST1, the IgIIIa exon of FGFR1, the IgIIIa and IgIIIIc exons of FGFR2, and the P250R site of FGFR3. The authors identified novel missense mutations in the TWIST box in 2 patients, 1 with coronal (601622.0013) and 1 with sagittal (601622.0014) synostosis.
Sweeney-Cox Syndrome
In an unrelated boy and girl with frontonasal dysplasia, hypertelorism, eyelid colobomas, and crumpled ears (Sweeney-Cox syndrome, SWCOS; 617746), Kim et al. (2017) identified heterozygous missense mutations in the TWIST1 gene, both involving the same residue: E117V (601622.0015) and E117G (601622.0016). Experiments in the C. elegans homolog gene hlh-8 suggested a predominantly dominant-negative mechanism for the action of amino acid substitutions at this highly conserved glutamic acid residue.
Possible Association with Auriculocondylar Syndrome 4
In a large 4-generation Brazilian family with auriculocondylar syndrome mapping to chromosome 7p21 (ARCND4; 620457), Romanelli Tavares et al. (2022) identified a 430-kb tandem duplication in the HDAC9 gene (606543.0001), telomeric to TWIST1 and covering most of the HDAC9 gene, that segregated fully with disease. Capture-C analysis of chromosome conformation revealed multiple cis interactions between the TWIST1 promoter and putative regulatory elements within the duplicated region. Patient-derived neural crest cells showed significant increases in HDAC9 and TWIST1 mRNA, and there was a significant decrease in migratory capacity of patient cells compared to controls. In addition, patient-derived mesenchymal stem cells showed significantly diminished ALP (see 171760) expression and enzymatic activity during osteogenic differentiation compared to control cells, and a subtle decrease in matrix mineralization was also observed in patient cells. The authors suggested that the 430-kb tandem duplication causes deregulation of TWIST1 expression, which results in development of ARCND features through compromised neural crest migration and osteogenic differentiation.
Heterozygous-null Twist mice have variable expression of craniofacial and limb defects consistent with the phenotype and variability seen in Saethre-Chotzen syndrome (Bourgeois et al., 1998).
Mice heterozygous for the ethylmethanesulfonate (EMS)-induced polydactyly ems (pde) mutation show preaxial polydactyly of the hindlimbs. Browning et al. (2001) determined that the pde mutation maps to chromosome 12 and is an allele of Twist. However, sequencing the Twist protein-coding region and several hundred basepairs upstream of the coding region failed to reveal a disease-associated mutation. Browning et al. (2001) concluded that the lesion may be in a regulatory element of the gene.
Pan et al. (2009) found that homozygous Twist1 knockout in mice was embryonic lethal. Twist1 +/- mice were resistant to obesity when placed on a high-fat diet and showed substantially less lipid accumulation in brown fat compared with wildtype animals. The brown fat of Twist1 +/- mice showed elevated oxygen consumption and mitochondrial biogenesis, and Twist1 +/- mice exhibited elevated nighttime, but not daytime, body temperature.
In each of 5 families with Saethre-Chotzen syndrome (SCS; 101400), Howard et al. (1997) found that a unique mutation of the TWIST gene segregated with the disorder. One mutation was a single adenosine nucleotide insertion predicted to result in a frameshift and premature termination of the protein prior to the DNA-binding domain. This tyr103-to-ter (Y103X) mutation, which they designated Y103STOP, created a truncated protein lacking the basic and helix-loop-helix domains. A father and his daughter with the Y103STOP mutation had all the classic features of SCS as well as cleft palate, short stature, and learning disabilities requiring special education. Patients with the other mutations had fewer of the associated anomalies and no cognitive problems.
In affected members of a family with Saethre-Chotzen syndrome (SCS; 101400), Howard et al. (1997) demonstrated a Q119P (gln119-to-pro) mutation in the TWIST gene that most likely resulted in the disruption of the alpha helix in the DNA-binding domain. Therefore, they predicted that the mutation would alter or abolish the ability of this mutant TWIST to bind DNA.
In patients with Saethre-Chotzen syndrome (SCS; 101400), El Ghouzzi et al. (1997) identified heterozygosity for 3 nonsense mutations of the TWIST gene. One of these, tyr107 to ter (Y107X), was predicted to result in translation termination upstream of the first helix of the bHLH domain of protein. See also 601622.0004 and 601622.0005.
In patients with Saethre-Chotzen syndrome (SCS; 101400), El Ghouzzi et al. (1997) identified a TCG-to-TAG (ser127-to-ter) nonsense mutation in the TWIST gene predicted to result in translation termination within the first helix of the bHLH domain of the protein.
In a patient with Saethre-Chotzen syndrome (SCS; 101400), El Ghouzzi et al. (1997) identified a GAG-to-CAG transversion of the TWIST gene predicted to result in translation termination within the first helix of the bHLH domain of the protein.
In a patient with Saethre-Chotzen syndrome (SCS; 101400), El Ghouzzi et al. (1997) demonstrated heterozygosity for a T-to-C transition in the TWIST gene, changing codon 135 from CTG (leu) to CCG (pro). The mutation was located within the first helix of the bHLH domain of the protein and affected a highly conserved amino acid.
In 3 unrelated patients with Saethre-Chotzen syndrome (SCS; 101400), Rose et al. (1997) identified a 21-bp duplication in the TWIST gene. The authors stated that a total of 8 such duplications had been found in which 5 different nucleotides, spread across 16 bases, had been identified as a start point of the duplication. The start points of the 3 duplications found in this study were nucleotides 418, 419, and 421. In the cases of 418 and 421, the duplication involved the addition of 7 amino acids; in the case of 419, it resulted in a premature stop at codon 139. The remarkably large number of duplications suggested a mechanism involving misalignment of a directly repeated sequence 21 bp apart. El Ghouzzi et al. (1997) had reported 2 hexanucleotide repeats 21 bp apart close to the duplication start points.
Gripp et al. (1999) described an E181X (glu181-to-ter) mutation in the TWIST gene, predicted to lead to premature termination of the protein carboxy-terminal to the helix 2 domain, in a child with cranial synostosis and unilateral radial aplasia. The diagnosis of Baller-Gerold syndrome (218600) was entertained. After the TWIST mutation was discovered, which pointed to the diagnosis of Saethre-Chotzen syndrome (SCS; 101400), the whole family was investigated. Facial asymmetry, prominent nose, high palate, and hallux valgus observed in the father and older sister were consistent with mild presentation of SCS and these 2 individuals were found also to carry the TWIST mutation.
In a proband and his mother affected with Robinow-Sorauf syndrome (180750), Kunz et al. (1999) reported a 1-bp insertion at position 460-461 in the second triplet of the helix II domain, resulting in a frameshift and a stop codon at position 864, and elongating the putative protein product by 88 amino acids. The authors considered this mutation evidence that Robinow-Sorauf syndrome is at least allelic to Saethre-Chotzen syndrome (SCS; 101400), if not part of the phenotypic spectrum of that syndrome, rather than a separate disease entity.
Cai et al. (2003) suggested that the diagnosis of Robinow-Sorauf syndrome in the family reported by Kunz et al. (1999) could be questioned because the affected individuals lacked certain characteristics, such as syndactyly, that were found repeatedly in all members of the original Robinow-Sorauf pedigree.
Seto et al. (2001) reported a male patient with features typically associated with Baller-Gerold syndrome (218600), including metopic, sagittal, and coronal craniosynostosis and bilateral radial ray hypoplasia, along with other features, including small, round ears with prominent crus helices and cervical anomalies. The patient was found to have an A-to-G transition at nucleotide 466 in the conserved helix II domain of the TWIST gene, resulting in an ile156-to-val (I156V) substitution. The father, who also carried the mutation, had very mild features of Saethre-Chotzen syndrome (SCS; 101400). Seto et al. (2001) suggested that some cases of Baller-Gerold syndrome should be reclassified as a heterogeneous form of Saethre-Chotzen syndrome.
Dollfus et al. (2001) identified a gln28-to-ter (Q28X) mutation in the TWIST gene in a large Indian family, initially referred because of prominent palpebral anomalies in some members (Maw et al., 1996) sharing features in common with the BPES syndrome (110100). Indeed this was considered to be a separate form of BPES (BPES3). After clinical reappraisal of all members of the family, some of whom were not born at the time of the initial linkage analysis, Dollfus et al. (2002) concluded that the phenotypic expression was compatible with Saethre-Chotzen syndrome (SCS; 101400), with remarkable phenotypic variability. Only 4 of the 16 patients examined showed obvious craniostenosis, namely, oxycephaly. The penetrance of craniosynostosis was lower than previously reported for SCS. Fifteen patients (93%) had moderate to severe ptosis. Minor limb and external ear abnormalities were present in most. Eyelid features were the hallmark of the disease for 12 members of the family, suggesting that mutations in TWIST may lead to a phenotype with mainly palpebral features and no craniostenosis. This phenotypic variability could be the result of modifier genes and/or genetic background effect, as noticed previously in the transgenic Twist-null heterozygous mice.
Cai et al. (2003) restudied the original family reported by Robinow and Sorauf (1975) and identified heterozygosity for a 221C-T transition in the TWIST gene, resulting in a premature stop codon at amino acid position 71 (Q71X). Cai et al. (2003) stated that they examined 3 of the 11 affected members of the original family with Robinow-Sorauf syndrome (180750) in addition to the propositus and found that all had second interdigital syndactyly as well as a toe deformity (either polydactyly or hallux valgus). Cai et al. (2003) stated that the reported 'Robinow-Sorauf' families are examples of variable expression of the TWIST mutant phenotype and provide further proof that the 'Robinow-Sorauf' syndrome lies within the spectrum of the SCS syndrome.
In a male infant with isolated synostosis of the right coronal suture (CRS1; 123100), Seto et al. (2007) identified heterozygosity for a 556G-T transversion in the C-terminal box of the TWIST1 gene, resulting in an ala186-to-thr (A186T) substitution. The patient had no facial anomalies other than the associated facial asymmetry, no 2-3 syndactyly, and neurologic status was normal, although at 18 months of age his mental and psychomotor development was in the low average to mildly delayed range. The mutation was not found in either parent, and there was no family history of craniosynostosis.
In a male infant with isolated synostosis of the sagittal suture (CRS1; 123100), Seto et al. (2007) identified heterozygosity for a 563C-T transition in the C-terminal box of the TWIST1 gene, resulting in an ser188-to-leu (S188L) substitution. The patient had no facial anomalies or 2-3 syndactyly, and neurologic status was normal, although at 24 months of age his mental and psychomotor development was mildly delayed. The unaffected father also carried the mutation; both father and son had small, square-shaped ears.
In a boy with Sweeney-Cox syndrome (SWCOS; 617746), previously reported as 'family 18' by Miller et al. (2017), Kim et al. (2017) demonstrated heterozygosity for a de novo c.350A-T transversion (chr7:19,116,972A-T) in the TWIST1 gene, resulting in a glu117-to-val (E117V) substitution at a highly conserved residue within the basic DNA binding domain. The mutation was not present in either of his biologically confirmed unaffected parents.
In a girl with Sweeney-Cox syndrome (SWCOS; 617746), Kim et al. (2017) identified heterozygosity for a de novo c.350A-G transition (chr7:19,116,972A-G) in the TWIST1 gene, resulting in a glu117-to-gly (E117G) substitution at a highly conserved residue within the basic DNA binding domain. The mutation was not present in either of her unaffected parents.
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