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

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

Author information

1
Ambulantes Gesundheitszentrum der Charité-Universitätsmedizin Berlin, Berlin, Germany.
2
1] Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
3
1] Institute of Human Genetics, University of Ulm, Ulm, Germany [2] Department of Biotechnology and Informatics, BUITEMS, Quetta, Pakistan.
4
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
5
Pediatric Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
6
Department of Biotechnology and Informatics, BUITEMS, Quetta, Pakistan.
7
Department of Genetics, Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hopital Necker-Enfants Malades, Paris, France.
8
1] Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
9
Institute of Human Genetics, University of Ulm, Ulm, Germany.
10
1] Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Institute for Human Genetics, University of Würzburg, Würzburg, Germany.
11
Julius-von-Sachs Institute, University of Würzburg, Würzburg, Germany.

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.

PMID:
24129431
PMCID:
PMC4023204
DOI:
10.1038/ejhg.2013.222
[Indexed for MEDLINE]
Free PMC Article

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