title: Association between nonsyndromic cleft lip with or without cleft palate and the glutamic acid decarboxylase 67 gene in the Japanese population.
abstract: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is one of the most common craniofacial malformations. Both genetic and environmental factors are involved in the pathogenesis. In addition to its role as an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) synthesized by glutamic acid decarboxylase (GAD) is presumed to play a role in normal embryonic, especially facial, development. This notion has been substantiated by the fact that Gad67 knockout mice have been shown to have cleft palate. We hypothesized that GAD67 may be involved in the development of NSCLP and investigated the possible association between the GAD67 gene (GAD67) and NSCLP in Japanese patients. We screened 50 probands for single nucleotide polymorphisms (SNPs) in GAD67 using denaturing high performance liquid chromatography (DHPLC) and found seven SNPs. Since two SNPs showed complete linkage disequilibrium (LD) to the other SNPs, we constructed a 5-locus haplotype of GAD67. The frequency distribution of the haplotype differed between NSCLP patients and controls (P = 0.0028). The frequency of -445A, -292A, -147G, 111C, and IVS9-39T haplotype in the NSCLP patients was significantly lower than that in controls (P = 0.00098). In a transmission disequilibrium test (TDT) in 99 parent-offspring trios, we found -445C, -292C, -147G, 111C, and IVS9-39C haplotype was preferentially transmitted to the patients with cleft lip and palate (P = 0.0077). Our data suggest that GAD67 is involved in the pathogenesis of NSCLP in the Japanese population.
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.|Department of Plastic Surgery, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kanno
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Plastic Surgery, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
mesh_terms: D044466:Asian People; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D016172:DNA Fingerprinting; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D015810:Linkage Disequilibrium; D009691:Nucleic Acid Denaturation; D010290:Parents; D020641:Polymorphism, Single Nucleotide; D011153:Population / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000235:genetics / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1