Non-Syndromic Cleft Palate in Mice

描述(由申请人提供)：哺乳动物继发性腭裂的发育是一个复杂而关键的过程，在人类中很容易受到干扰，导致常见的和令人痛苦的出生缺陷，腭裂(CP)。原发和/或继发腭裂是人类常见的先天畸形之一。尽管唇裂合并/不合并腭裂(CLIP)较为常见，但单纯性CP约占记录病例的三分之一。分离的CP被认为是一种具有重要遗传贡献的病原性异质性。虽然CP可与350多种特征性疾病有关，但超过50%的CP病例是孤立的(零星的)，并被认为没有其他异常(非综合征)。我们的长期目标集中在确定直接和/或间接(即遗传易感性和多因素原因)导致哺乳动物次级腭部形成失败的遗传决定因素(使用动物模型)，并更好地了解这些基因在正常次级腭部形成过程中在分子水平上所起的作用。人类和小鼠在腭部发育上的相似之处使后者成为研究腭部发育正常和缺陷的重要模式生物。转基因插入突变可以通过对内源基因的非同源破坏来促进对发育重要基因的识别。我们已经研究了四个不同的转基因小鼠，这些小鼠发生了常染色体隐性遗传性非综合征腭裂，涉及至少三个不同的基因座，位于第三和第四染色体上。本研究的重点是表征这些转基因插入导致基因组DNA中断的间隔，作为识别导致这些小鼠腭裂的中断基因的前奏。

DESCRIPTION (provided by applicant): Development of the mammalian secondary palate is a complex and critical process that in man can be easily perturbed leading to the common and distressing birth defect, cleft palate (CP). Clefts of the primary and/or secondary palates are consistently included among the more common congenital anomalies occurring in man. Even though the combination of cleft lip with/or without cleft palate (CLIP) is more commonly seen, isolated CP can account for approximately one-third of the documented cases. Isolated CP is considered to be an etiologically heterogeneous trait with an important genetic contribution. While CP can be associated with more that 350 characterized disorders, more than 50% of cases of CP occur as isolated (sporadic) and thought to be free of other anomalies (non-syndromic). Our long-term objectives focus on identifying genetic determinants that directly and/or indirectly (i.e. genetic susceptibility and multifactorial causes) contribute to the failure of mammalian secondary palate formation (using animal models) and to better understand the roles that these genes play at the molecular level during normal secondary palate formation. Similarities in palate development between humans and mice have allowed the later to be an important model organism for studying normal and defective palatogenesis. Transgene insertion mutagenesis can facilitate the identification of developmentally important genes through non-homologous disruption of endogenous genes. We have been investigating four separate lines of transgenic mice that develop autosomal recessive nonsyndromic cleft palate involving a least three distinct loci that localize to chromosomes 3 and 4. The focus of this research project is to characterize the interval of genomic DNA disrupted by these transgene insertions as a prelude to identifying the disrupted genes responsible for cleft palate in these mice.