Association between nonsyndromic cleft lip with or without cleft palate and the glutamic acid decarboxylase 67 gene in the Japanese population
Association between nonsyndromic cleft lip with or without cleft palate and the glutamic acid decarboxylase 67 gene in the Japanese population
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DOI：
10.1002/ajmg.a.20649
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发表时间：
2004-05-15
影响因子：
2
通讯作者：
Matsubara, Y
中科院分区：
文献类型：
--
作者：
Kanno, K;Suzuki, Y;Matsubara, Y
非综合征性唇裂伴或不伴腭裂(NSCLP)是最常见的颅面畸形之一。遗传因素和环境因素共同参与了发病过程。谷氨酸脱羧酶(GAD)合成的γ-氨基丁酸(GABA)除了作为抑制性神经递质外，还被认为在正常胚胎发育，特别是面部发育中发挥作用。Gad67基因敲除小鼠被证明患有腭裂，这一事实证实了这一观点。我们假设GAD67可能与NSCLP的发生有关，并研究了日本患者中GAD67基因(GAD67)与NSCLP之间的可能联系。应用变性高效液相色谱(DHPLC)技术对50个先证者进行GAD67基因单核苷酸多态(SNPs)筛查，发现7个SNPs。由于两个SNPs与另外两个SNPs表现出完全连锁不平衡(LD)，我们构建了GAD67的一个5位点单倍型。单倍型频率分布在非小细胞肺癌患者和对照组之间差异有统计学意义(P=0.0028)。NSCLP组-445A、-292A、-147G、111C和IVS9-39T单倍型频率显著低于对照组(P=0.00098)。对99个亲子三组进行传递不平衡检验，发现-445C、-292C、-147G、111C单倍型优先传递给唇腭裂患者(P=0.0077)。我们的数据表明，GAD67参与了日本人NSCLP的发病机制。(C)2003年Wiley-Liss，Inc.
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-aminobuty-ric 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 disequilibriurn (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. (C) 2003 Wiley-Liss, Inc.