Recessive Robinow Syndrome, Allelic to Dominant Brachydactyly Type B, Is Caused by Mutation of ROR2

Nat Genet. 2000 Aug;25(4):419-22. doi: 10.1038/78107.

Abstract

The autosomal recessive form of Robinow syndrome (RRS; MIM 268310) is a severe skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly and a dysmorphic facial appearance. We previously mapped the gene mutated in RRS to chromosome 9q22 (ref. 4), a region that overlaps the locus for autosomal dominant brachydactyly type B (refs 5,6). The recent identification of ROR2, encoding an orphan receptor tyrosine kinase, as the gene mutated in brachydactyly type B (BDB1; ref. 7) and the mesomelic dwarfing in mice homozygous for a lacZ and/or a neo insertion into Ror2 (refs 8,9) made this gene a candidate for RRS. Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3' regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggests that RRS is caused by loss of ROR2 activity. The identification of mutations in three distinct domains (containing Frizzled-like, kringle and tyrosine kinase motifs) indicates that these are all essential for ROR2 function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Alleles
  • DNA / chemistry
  • DNA / genetics
  • DNA Mutational Analysis
  • Face / abnormalities
  • Genes, Dominant
  • Genes, Recessive
  • Humans
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / pathology
  • Molecular Sequence Data
  • Mutation
  • Polymorphism, Restriction Fragment Length
  • Polymorphism, Single-Stranded Conformational
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Receptors, Cell Surface / genetics*
  • Syndactyly
  • Syndrome

Substances

  • Receptors, Cell Surface
  • DNA
  • ROR2 protein, human
  • Receptor Protein-Tyrosine Kinases
  • Receptor Tyrosine Kinase-like Orphan Receptors

Associated data

  • GENBANK/M97639