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
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
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DOI：
10.1002/bdra.20302
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发表时间：
2006-08-01
影响因子：
--
通讯作者：
Lidral, Andrew C.
中科院分区：
文献类型：
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作者：
Juriloff, Diana M.;Harris, Muriel J.;Lidral, Andrew C.
背景：非综合征性唇裂伴或不伴腭裂（CLP）是一种常见的人类先天性缺陷，具有复杂的遗传病因。其中一个未知基因位于染色体17q21上。小鼠毒株A/WySn具有具有复杂遗传病因的CLP，模仿人类缺陷，其1个致病基因clf1映射到与人类17q21同源的区域。对候选区域的广泛研究指出，来自基因Wnt9b的TAP转座子3'的新插入作为clf1突变。据报道，Wnt9b的隐性敲除突变（Wnt9b(-)）可引起包括一些CLP在内的致死性综合征。方法：对clf1与Wnt9b-突变的等位基因进行标准基因检测。Wnt9b(-)/+雄性与A/WySn雌性杂交的F1妊娠第14天（GD 14）胚胎共83个，与A/WySn雌性回交的F1 Wnt9b(-)/clf1雄性与A/WySn雌性回交的BC1 GD 14胚胎共79个。通过DNA标记获得clf1和Wnt9b的胚胎基因型。来自a /WySn的第二个非连锁修饰位点clf2的基因型也得到了类似的结果。结果：复合突变胚（Wnt9b(-)/clf1）具有较高的CL频率：171为27%，BC1为63%。clf2修饰基因在本研究中发现有3个等位基因分离，并强烈影响CL在复合突变体中的外显率。结论：clf1与Wnt9b-的不互补证实了clf1是Wnt9b基因的突变。同源的人类WNT9B基因和3'保守的非编码区应检查在人类非综合征性CLP中的作用。
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 17q2l. Extensive studies of the candidate region pointed to a novel insertion of an TAP 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 171 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.