Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B

Inherited limb malformations provide a valuable resource for the identification of genes involved in limb development(1,2). Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies(3) and characterized by terminal deficiency of the fingers and toes. In the typical form of BDB, the thumbs and big toes are spared, sometimes with broadening or partial duplication(4-8). The BDB1 locus was previously mapped to chromosome 9q22 within an interval of 7.5 cM (refs 9, 10). Here we describe mutations in ROR2, which encodes the orphan receptor tyrosine kinase ROR2 (ref. 11), in three unrelated families with BDB1. We identified distinct heterozygous mutations (2 nonsense, 1 frameshift) within a 7-amino-acid segment of the 943-amino-acid protein, all of which predict truncation of the intracellular portion of the protein immediately after the tyrosine kinase domain. The localized nature of these mutations suggests that they confer a specific gain of function. We obtained further evidence for this by demonstrating that two patients heterozygous for 9q22 deletions including ROR2 do not exhibit BDB. Expression of the mouse orthologue, Ror2, early in limb development indicates that BDB arises as a primary defect of skeletal patterning.