The mutational spectrum of brachydactyly type C

Everman, David B.; Bartels, Cynthia F.; Yang, Yongmei; Yanamandra, Niranjan; Goodman, Frances R.; Mendoza‐Londono, Roberto; Savarirayan, Ravi; White, Susan; Graham, John M.; Gale, Robert Peter; Svarch, Eva; Newman, William G.; Kleckers, Albert R.; Francomano, Clair A.; Vinukonda, Govindaiah; Singh, Lalji; Morrison, Stuart C.; Thomas, J. Terrig; Warman, Matthew L.

doi:10.1002/ajmg.10777

Cited by 79 publications

(103 citation statements)

References 25 publications

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“…The R438C missense mutation is likely to alter the secondary structure of this growth factor by leading to aberrant inter-or intrachain disulfide linkages that form within the highly conserved active domain. Heterolo- gous expression of the R438C mutation in mammalian cells results in a protein that forms high molecular weight aggregates and appears to be poorly secreted [4]. Although this mutation has been reported previously in two families with brachydactyly type C [4,12], these families were not noted to have the broad phenotypic expression of hand and feet abnormalities found in our family.…”

Section: Discussioncontrasting

confidence: 54%

“…Nonpenetrance has been previously reported in families with brachydactyly type C [4]. Interestingly, the nonpenetrant individuals may be clinically unaffected, or may have other skeletal abnormalities, such as CVT, as was seen in the proband of family F. Indeed, metacarpophalangeal profiling, a technique that can be used to identify subclinical manifestation of disease, did not demonstrate typical findings of brachydactyly type C (greater than 3 standard deviations below the mean) in two members of our family inheriting the R438C CDMP-1 mutation.…”

Section: Discussionmentioning

confidence: 85%

“…Our family (family F) manifests similar variability in skeletal abnormalities but carries a different mutation. The functional mechanism of both mutations is predicted to be haploinsufficiency, but the exact effect of the R438C mutation is unknown and a dominant negative or gain of function effect of this mutation cannot be ruled out [4]. Our data gives further evidence for the importance of additional genetic or environmental factors in the variable expressivity seen in some families with the CDMP-1 syndrome of hand Table 1 Metacarpophalangeal profile of proband of family F (IV:l), her unaffected father who carries the same R428C CDMP-1 mutation (111:2), and mean profile of affected individuals from a single family with brachydactyly type C r131 Numbers reflect the standard deviation (SD) from age and sex matched standards [7].…”

Section: Discussionmentioning

confidence: 99%

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Variable hand and foot abnormalities in family with congenital vertical talus and CDMP-1 gene mutation

et al. 2005

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Isolated foot anomalies, including congenital vertical talus, were shown recently to occur in heterozygous carriers of CDMP-1 (cartilage-derived morphogenetic protein-1) gene mutations. Six families with isolated congenital vertical talus with apparent autosoma1 dominant inheritance were ascertained. DNA was isolated from 17 affected individuals and 24 unaffected individuals from these families and subjected to mutational analysis of the CDMP-1 gene. A missense mutation was identified (1312C>T) that results in an R438C substitution in the CDMP-1 active domain. This segregated with disease in one Northeren American family. Phenotypic variability in this family includes brachydactyly type C, clinodactyly, calcaneo valgus deformity, and congenital vertical talus. Metacarpophalangeal profiles (MCPPs) confirm incomplete penetrance in one family member. Hence, CDMP-1 mutations may be found in individuals with apparently isolated CVT, although careful examination of family members may reveal additional, subtle hand and foot abnormalities. However, mutations in CDMP-1 do not appear to be a frequent cause of isolated congenital vertical talus.

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Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Variable hand and foot abnormalities in family with congenital vertical talus and CDMP-1 gene mutation

et al. 2005

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“…Ring fingers are only mildly affected and hyperphalangy of the index and middle fingers might occur. 9,[18][19][20] However, clinical phenotypes resulting from heterozygous BMPR1B and GDF5 mutations are variable and also show overlapping features. 21,22 Here we present two consanguineous families segregating as yet unreported mutations in BMPR1B (c.157T4C, p.(C53R) and (c.657G4A, p.(W219*)) with a total of three affected individuals carrying the respective mutations in a homozygous state.…”

Section: Introductionmentioning

confidence: 99%

Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe

et al. 2013

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Acromesomelic chondrodysplasias (ACDs) are characterized by disproportionate shortening of the appendicular skeleton, predominantly affecting the middle (forearms and forelegs) and distal segments (hands and feet). Here, we present two consanguineous families with missense (c.157T4C, p.(C53R)) or nonsense (c.657G4A, p.(W219*)) mutations in BMPR1B. Homozygous affected individuals show clinical and radiographic findings consistent with ACD-type Grebe. Functional analysis of the missense mutation C53R revealed that the mutated receptor was partially located at the cell membrane. In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay. Further, overexpression of the C53R mutation in an in vitro chondrogenesis assay showed no effect on cell differentiation, indicating a loss of function. The nonsense mutation (c.657G4A, p.(W219*)) introduces a premature stop codon, which is predicted to be subject to nonsense-mediated mRNA decay, causing reduced protein translation of the mutant allele. A lossof-function effect of both mutations causing recessive ACD-type Grebe is further supported by the mild brachydactyly or even non-penetrance of these mutations observed in the heterozygous parents. In contrast, dominant-negative BMPR1B mutations described previously are associated with autosomal-dominant brachydactyly-type A2.

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“…3 Heterozygous carriers of growth differentiation factor 5 (GDF5) loss-of-function mutations are typically affected by brachydactyly type C (BDC). 4,5 The BDC phenotype includes brachymesophalangy of fingers II, III and V. Finger IV is usually unaffected and thus appears as the longest finger of the hand. Shortening of metacarpals I and hyperphalangy in fingers II and III may occur and can be considered as relatively characteristic signs.…”

Section: Introductionmentioning

confidence: 99%

A novel R486Q mutation in BMPR1B resulting in either a brachydactyly type C/symphalangism-like phenotype or brachydactyly type A2

et al. 2006

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Heterozygous missense mutations in the serine-threonine kinase receptor BMPR1B result typically in brachydactyly type A2 (BDA2), whereas mutations in the corresponding ligand GDF5 cause brachydactyly type C (BDC). Mutations in the GDF inhibitor Noggin (NOG) or activating mutations in GDF5 cause proximal symphalangism (SYM1). Here, we describe a novel mutation in BMPR1B (R486Q) that is associated with either BDA2 or a BDC/SYM1-like phenotype. Functional investigations of the R486Q mutation were performed and compared with the previously reported BDA2-causing mutation R486W and WT BMPR1B. Overexpression of the mutant receptors in chicken micromass cultures resulted in a strong inhibition of chondrogenesis with the R486Q mutant, showing a stronger effect than the R486W mutant. To investigate the consequences of the BMPR1B mutations on the intracellular signal transduction, we used stably transfected C2C12 cells and measured the activity of SMAD-dependent and SMAD-independent pathways. SMAD activation after stimulation with GDF5 was suppressed in both mutants. Alkaline phosphatase induction showed an almost complete loss of activation by both mutants. Our data extend the previously known mutational and phenotypic spectrum associated with mutations in BMPR1B. Disturbances of NOG-GDF5-BMPR1B signaling cascade can result in similar clinical manifestations depending on the quantitative effect and mode of action of the specific mutations within the same functional pathway.

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The mutational spectrum of brachydactyly type C

Cited by 79 publications

References 25 publications

Variable hand and foot abnormalities in family with congenital vertical talus and CDMP-1 gene mutation

Variable hand and foot abnormalities in family with congenital vertical talus and CDMP-1 gene mutation

Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe

A novel R486Q mutation in BMPR1B resulting in either a brachydactyly type C/symphalangism-like phenotype or brachydactyly type A2

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