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Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. Recently, heterozygous mutations of the orphan receptor tyrosine kinase (TK) ROR2, located within a distinct segment directly after the TK domain, have been shown to be responsible for BDB. We report four novel mutations in ROR2 (two frameshifts, one splice mutation, and one nonsense mutation) in five families with BDB. The mutations predict truncation of the protein within two distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients affected with the distal mutations have a more severe phenotype than do those with the proximal mutation. Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK domain. His phenotype resembles an extreme form of brachydactyly, with extensive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he has vertebral anomalies, brachymelia of the arms, and a ventricular septal defect-features that are reminiscent of Robinow syndrome, which has also been shown to be caused by mutations in ROR2. The BDB phenotype, as well as the location and the nature of the BDB mutations, suggests a specific mutational effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome.

Original publication

DOI

10.1086/303084

Type

Journal article

Journal

Am J Hum Genet

Publication Date

10/2000

Volume

67

Pages

822 - 831

Keywords

Amino Acid Sequence, Base Sequence, Codon, Nonsense, Consanguinity, DNA Mutational Analysis, Exons, Female, Fingers, Frameshift Mutation, Genotype, Hand Deformities, Congenital, Humans, Introns, Male, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Protein Structure, Tertiary, RNA Splice Sites, Receptor Protein-Tyrosine Kinases, Receptor Tyrosine Kinase-like Orphan Receptors, Receptors, Cell Surface, Syndrome