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

Abstract

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.

Genetics of human isolated acromesomelic dysplasia

“…To date, twenty pathogenic mutations in the gene GDF5 including five in patients affected with AMDG have been reported (Table 2) Faiyaz-Ul-Haque et al, 2002; Al-Yahyaee Basit et al, 2008;Martinez-Garcia et al, 2015). Recently, Graul-Neumann et al (Graul-Neumann et al, 2014). have reported mutations (p.Cys53Arg; p.Try219*) in the gene BMPR1B causing AMDG in two consanguineous families of Lebanon and Pakistani origin (Table 2).…”

“…It was localized to chromosome 20q11.22 (Thomas et al, 1996) and subsequently small mutations in the growth and differentiation factor-5 (GDF5) gene were detected in several families (Thomas et al, 1996). Recently, point mutations in bone morphogenetic protein receptor IB (BMPR1B) gene have been identified in families segregating AMDG (Graul-Neumann et al, 2014). Similarly, AMDH is characterized by severe dwarfism, lower limbs more affected than upper limbes and large joint dislocations.…”

A novel homozygous variant in BMPR1B underlies acromesomelic dysplasia Hunter–Thompson type

“…A homozygous nonsense variant (p.Trp219*) in the same domain, in a family of Pakistani origin reported by Graul‐Neumann et al. (), caused more severe form of acromesomelic dysplasia, AMDG. It is highly likely that the nonsense variant in the kinase domain results in complete loss of function of protein through nonsense‐mediated mRNA decay and/or protein truncation.…”

Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility

“…In some but not all heterozygotes much milder forms of the traits were seen. BMPR1B is already associated with bone dysmorphologies [1][2][3], but PDHA2 has not been associated with any disease. The loci for syndromes manifesting with digit anomalies and infertility together, such as Dauwerse-Peters syndrome (MIM 611733; t(4;6)(q12;p23)), deafnessinfertility syndrome (MIM 611102; 15q15.30), and short stature, onychodysplasia, facial dysmorphism and hypotrichosis syndrome (SOFT; MIM 614813; 3p21) are all excluded by linkage analysis.…”

“…The skeletal phenotype of the patient was aplasia of the fibula, severe brachydactyly, ulnar deviation of the hands, fusion of carpal/tarsal bones and disproportionate short stature, and the variant was homozygous 8-bp deletion c.361_368delGGACCTAT (p.(Gly121Thrfs*13)). The manifestations of two other variants, namely, c.157T>C (p.(Cys53Arg)) and c.657G>A (p.(Trp219*)), are also like Grebe chondrodysplasia [2]. The last variant c.91C>T (p. (Arg31Cys)) was assessed to have a moderate impact on the protein and accordingly caused fibular hypoplasia and complex brachydactyly (du Pan dysplasia), a milder ACD [3].…”