Non-Syndromic Cleft Palate in Mice

描述（由申请人提供）：哺乳动物次生腭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，导致常见和令人痛苦的出生缺陷，腭裂（CP）。唇腭裂是人类常见的先天性畸形之一，虽然唇裂合并腭裂（CLIP）的情况更为常见，但单独的腭裂约占所有病例的三分之一。孤立CP被认为是一种病因异质性性状，具有重要的遗传贡献。虽然CP可以与超过350种特征性疾病相关，但超过50%的CP病例是孤立的（散发性），并且被认为没有其他异常（非综合征性）。我们的长期目标集中在确定遗传因素，直接和/或间接（即遗传易感性和多因素的原因）有助于哺乳动物继发腭形成失败（使用动物模型），并更好地了解这些基因在分子水平上发挥的作用，在正常的继发腭形成。人类和小鼠腭发育的相似性使后者成为研究正常和有缺陷的腭发生的重要模式生物。转基因插入突变可以通过内源基因的非同源破坏来促进发育重要基因的鉴定。我们一直在调查四个独立的系的转基因小鼠，发展常染色体隐性遗传性非综合征腭裂涉及至少三个不同的位点，定位于染色体3和4。该研究项目的重点是表征这些转基因插入破坏的基因组DNA的间隔，作为鉴定这些小鼠中导致腭裂的破坏基因的前奏。

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.