title: A mutation in RYK is a genetic factor for nonsyndromic cleft lip and palate.
abstract: OBJECTIVE
  The RYK, EPHB2, and EPHB3 genes are attractive candidates for cleft lip and/or palate and cleft palate only pathogenesis. Both the Ryk-deficient mouse and Ephb2/Ephb3 (genes for interaction molecules with RYK) double-mutant mouse show cleft palate.
  
  
  METHODS
  Mutation searches for RYK, EPHB2, and EPHB3 were carried out in a large number of Japanese and Vietnamese patients with cleft lip and/or palate and cleft palate only. Case-control study and transmission disequilibrium tests were performed also, using three single nucleotide polymorphisms within a linkage disequilibrium block in RYK. Seven haplotypes were constructed from the single nucleotide polymorphisms.
  
  
  RESULTS
  A missense mutation, 1355G>A (Y452C), in RYK was identified in one Vietnamese patient with cleft lip and/or palate. This mutation was not found among 1646 Vietnamese, Japanese, and Caucasians, including 354 cleft lip and/ or palate and cleft palate only patients. Colony formation assay using NIH3T3 cells transfected with mutant cDNA revealed that mutant RYK had significantly reduced protein activity, compared with those with wild-type RYK, implying that the transformation ability of RYK is depleted by this mutation. Although a case-control study and transmission disequilibrium tests on three individual single nucleotide polymorphisms provided no evidence for association with oral clefts, a case-control study on one rare haplotype suggested a positive association in Japanese patients with cleft lip and/or palate and cleft palate only. No mutations in EPHB2 and EPHB3 were found in any patients examined.
  
  
  CONCLUSIONS
  The findings suggested that a missense mutation, 1355G>A, and one rare single nucleotide polymorphisms haplotype may play a role in the development of cleft lip and/or palate in the Vietnamese, and cleft lip and/ or palate and cleft palate only in the Japanese.
authors: The Second Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Chiba, Japan.
authors: Akira
authors: A
authors: Watanabe
authors: Sadanori
authors: S
authors: Akita
authors: Nguyen Thi Duc
authors: NT
authors: Tin
authors: Nagato
authors: N
authors: Natsume
authors: Yoko
authors: Y
authors: Nakano
authors: Norio
authors: N
authors: Niikawa
authors: Takeshi
authors: T
authors: Uchiyama
authors: Koh-ichiro
authors: K
authors: Yoshiura