BMPR1B – Acromesomelic Dysplasia Type A2

Acromesomelic dysplasia type A2 is an autosomal recessive skeletal disorder characterized by disproportionate shortening of the middle and distal limb segments with preservation of the axial skeleton. The gene BMPR1B encodes a type I bone morphogenetic protein receptor mediating GDF5 signaling. While most cases of acromesomelic chondrodysplasia arise from biallelic loss-of-function mutations in GDF5, rare hypomorphic or null BMPR1B alleles have been shown to cause the milder du Pan and Grebe phenotypes within the spectrum of Acromesomelic Dysplasia Type A2.

Disease-causing BMPR1B variants have been identified in three unrelated consanguineous families. A homozygous c.91C>T (p.Arg31Cys) variant was reported in an adult woman with du Pan dysplasia ([PMID:26105076]). A novel homozygous c.1111C>T (p.Arg371Ter) nonsense mutation was found in two affected siblings with Grebe-type acromesomelic dysplasia in a Moroccan family ([PMID:37524292]). Additionally, two consanguineous families harbored homozygous c.157T>C (p.Cys53Arg) or c.657G>A (p.Trp219Ter) variants causing Grebe-type disease ([PMID:24129431]). In total, four probands across three families demonstrate autosomal recessive inheritance and segregation of BMPR1B alleles ([PMID:26105076]; [PMID:37524292]; [PMID:24129431]).

The variant spectrum includes missense substitutions in the ligand-binding domain (p.Arg31Cys, p.Cys53Arg) and premature stop codons predicted to undergo nonsense-mediated decay (p.Arg371Ter, p.Trp219Ter). Functional analyses reveal that p.Arg31Cys is hypomorphic with significant residual activity, whereas p.Cys53Arg leads to more profound loss-of-function correlating with phenotype severity ([PMID:26105076]).

Multiple cell-based assays corroborate the pathogenic mechanism. Luciferase reporter experiments and chondrogenesis assays in micromass cultures demonstrate that hypomorphic and null BMPR1B variants impair SMAD1/5/8 phosphorylation and cartilage differentiation. Structural modeling supports disruption of receptor activation by these alleles ([PMID:26105076]; [PMID:24129431]).

The concordance of homozygosity segregation, segregation in consanguineous pedigrees, and consistent functional deficits across variants fulfills strong genetic and experimental criteria for a Definitive gene–disease relationship. The graded impact of hypomorphic versus null alleles provides a mechanistic basis for the spectrum of acromesomelic dysplasias.

Key take-home: BMPR1B sequencing should be included in diagnostic panels for autosomal recessive acromesomelic dysplasia, with variant interpretation guided by functional evidence.

References

• Orphanet journal of rare diseases • 2015 • A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia. PMID:26105076
• Bone • 2023 • A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias. PMID:37524292
• European journal of human genetics : EJHG • 2014 • Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe. PMID:24129431

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