title: Wnt9b is the mutated gene involved in multifactorial nonsyndromic cleft lip with or without cleft palate in A/WySn mice, as confirmed by a genetic complementation test.
abstract: BACKGROUND
  Nonsyndromic cleft lip (CL) with or without cleft palate (CLP) is a common human birth defect with complex genetic etiology. One of the unidentified genes maps to chromosome 17q21. A mouse strain, A/WySn, has CLP with complex genetic etiology that models the human defect, and 1 of its causative genes, clf1, maps to a region homologous to human 17q21. Extensive studies of the candidate region pointed to a novel insertion of an IAP transposon 3' from the gene Wnt9b as the clf1 mutation. Independently a recessive knockout mutation of Wnt9b (Wnt9b-) was reported to cause a lethal syndrome that includes some CLP.
  
  
  METHODS
  A standard genetic test of allelism between clf1 and the Wnt9b- mutation was done. A total of 83 F1 embryos at gestation day 14 (GD 14) from Wnt9b-/+ males crossed with A/WySn females, and 79 BC1 GD 14 embryos from F1 Wnt9b-/clf1 males back-crossed to A/WySn females were observed for CL. Embryo genotypes at clf1 and Wnt9b were obtained from DNA markers. Genotypes for a second unlinked modifier locus from A/WySn, clf2, were similarly obtained.
  
  
  RESULTS
  The compound mutant embryos (Wnt9b-/clf1) had high frequencies of CL: 27% in the F1 and 63% in the BC1. The clf2 modifier gene was found to have 3 alleles segregating in this study and to strongly influence the penetrance of CL in the compound mutant.
  
  
  CONCLUSIONS
  The noncomplementation of clf1 and Wnt9b- confirms that clf1 is a mutation of the Wnt9b gene. The homologous human WNT9B gene and 3' conserved noncoding region should be examined for a role in human nonsyndromic CLP.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. juriloff@interchange.ubc.ca
authors.forename: Diana M
authors.initials: DM
authors.lastname: Juriloff
authors.forename: Muriel J
authors.initials: MJ
authors.lastname: Harris
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Carroll
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Lidral
mesh_terms: D000818:Animals; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005816:Genetic Complementation Test; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D012744:Sex Ratio; D051153:Wnt Proteins / Q000235:genetics*
chemical_list: D051153:Wnt Proteins