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

Eur J Hum Genet. 2014 Jun;22(6):726-33. doi: 10.1038/ejhg.2013.222. Epub 2013 Oct 16.

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.157T>C, p.(C53R)) or nonsense (c.657G>A, 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.657G>A, 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 loss-of-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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Bone Morphogenetic Protein Receptors, Type I / genetics*
  • Child, Preschool
  • Codon, Nonsense*
  • Consanguinity
  • DNA Mutational Analysis
  • Family Health
  • Female
  • Homozygote
  • Humans
  • Male
  • Mice
  • Molecular Sequence Data
  • Musculoskeletal Abnormalities / genetics*
  • Musculoskeletal Abnormalities / pathology
  • Mutation, Missense*
  • NIH 3T3 Cells
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / pathology
  • Pedigree
  • Phenotype
  • Sequence Homology, Amino Acid
  • Young Adult

Substances

  • Codon, Nonsense
  • BMPR1B protein, human
  • Bone Morphogenetic Protein Receptors, Type I

Supplementary concepts

  • Chondrodysplasia, Grebe type