RGD Reference Report - Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. - Rat Genome Database

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Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.

Authors: Lehmann, K  Seemann, P  Stricker, S  Sammar, M  Meyer, B  Suring, K  Majewski, F  Tinschert, S  Grzeschik, KH  Muller, D  Knaus, P  Nurnberg, P  Mundlos, S 
Citation: Lehmann K, etal., Proc Natl Acad Sci U S A 2003 Oct 14;100(21):12277-82. Epub 2003 Oct 01.
RGD ID: 1334470
Pubmed: PMID:14523231   (View Abstract at PubMed)
PMCID: PMC218749   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.2133476100   (Journal Full-text)

Brachydactyly (BD) type A2 is an autosomal dominant hand malformation characterized by shortening and lateral deviation of the index fingers and, to a variable degree, shortening and deviation of the first and second toes. We performed linkage analysis in two unrelated German families and mapped a locus for BD type A2 to 4q21-q25. This interval includes the gene bone morphogenetic protein receptor 1B (BMPR1B), a type I transmembrane serinethreonine kinase. In one family, we identified a T599 --> A mutation changing an isoleucine into a lysine residue (I200K) within the glycine/serine (GS) domain of BMPR1B, a region involved in phosphorylation of the receptor. In the other family we identified a C1456 --> T mutation leading to an arginine-to-tryptophan amino acid change (R486W) in a highly conserved region C-terminal of the BMPR1B kinase domain. An in vitro kinase assay showed that the I200K mutation is kinase-deficient, whereas the R486W mutation has normal kinase activity, indicating a different pathogenic mechanism. Functional analyses with a micromass culture system revealed a strong inhibition of chondrogenesis by both mutant receptors. Overexpression of mutant chBmpR1b in vivo in chick embryos by using a retroviral system resulted either in a BD phenotype with shortening and/or missing phalanges similar to the human phenotype or in severe hypoplasia of the entire limb. These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Congenital Limb Deformities  IAGP 1334470type A2 brachydactyly more ...RGD 
Congenital Limb Deformities  ISOBMPR1B (Homo sapiens)1334470; 1334470type A2 brachydactyly more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Bmpr1b  (bone morphogenetic protein receptor type 1B)

Genes (Mus musculus)
Bmpr1b  (bone morphogenetic protein receptor, type 1B)

Genes (Homo sapiens)
BMPR1B  (bone morphogenetic protein receptor type 1B)


Additional Information