BMPR1B – Brachydactyly Type A2

Brachydactyly type A2 (BDA2) is an autosomal dominant malformation characterized by hypoplasia or aplasia of the second middle phalanx of the index finger, lateral deviation of the digits, and variable involvement of toes. Linkage in two unrelated German pedigrees mapped BDA2 to 4q21–q25, identifying heterozygous BMPR1B variants as causal. Subsequent independent reports expanded the mutational spectrum to a third family, firmly establishing BMPR1B as the gene responsible for BDA2 (PMID:14523231; PMID:16957682).

Genetic evidence includes three heterozygous missense variants in unrelated probands with co-segregation in multigenerational pedigrees. In the first report, NM_001203.3:c.599T>A (p.Ile200Lys) and c.1456C>T (p.Arg486Trp) each segregated with BDA2 in two German families (n=6 affected relatives) (PMID:14523231). A later study described NM_001203.3:c.1457G>A (p.Arg486Gln) in a family with either BDA2 or overlapping brachydactyly type C/symphalangism phenotypes (PMID:16957682). All variants affect conserved residues in the glycine/serine-rich region or kinase domain of BMPR1B.

Variants are exclusively missense, cluster in functional domains, and include recurrent R486 substitutions. The I200K change abolishes kinase activity while R486W retains kinase function but exerts dominant-negative inhibition. The novel R486Q mutation shows stronger inhibition of chondrogenesis than R486W, correlating with phenotypic variability.

Functional assays demonstrate that I200K fails to phosphorylate downstream SMADs, whereas R486W and R486Q inhibit GDF5-induced signaling in micromass cultures. Retroviral overexpression of mutant chBmpR1b in chick limb buds recapitulates the BDA2 phenotype, confirming a dominant-negative mechanism disrupting cartilage formation (PMID:14523231; PMID:16957682).

No conflicting reports have disputed BMPR1B’s role in BDA2. The concordance of linkage, segregation, multiple independent variants, and robust functional data meets ClinGen criteria for a strong gene–disease association.

Key Take-home: Heterozygous missense variants in BMPR1B cause autosomal dominant brachydactyly type A2 via a dominant-negative mechanism, supporting BMPR1B sequencing in patients with concordant hand malformations for precise molecular diagnosis and genetic counseling.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2003 • Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. PMID:14523231
• European journal of human genetics : EJHG • 2006 • A novel R486Q mutation in BMPR1B resulting in either a brachydactyly type C/symphalangism-like phenotype or brachydactyly type A2. PMID:16957682

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