Dissecting the genetic complexity of human 6p deletion syndromes by using a region-specific, phenotype-driven mouse screen
Dissecting the genetic complexity of human 6p deletion syndromes by using a region-specific, phenotype-driven mouse screen
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DOI：
10.1073/pnas.0500584102
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发表时间：
2005-08-30
影响因子：
11.1
通讯作者：
Arkell, RM
中科院分区：
文献类型：
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作者：
Bogani, D;Willoughby, C;Arkell, RM
人类染色体 6p 末端区域的单体性导致多种先天性畸形，包括大脑、颅面和器官发生异常。为了检查这些表型的遗传基础，我们对小鼠基因组的同线区域（近端 Mmu13）进行了公正的功能分析。该区域隐性突变的基因筛查恢复了 13 个具有与各种临床病症相关表型的品系。其中包括两个导致前脑无裂畸形的基因座，两个导致无眼症的基因座，其中一个也导致其他颅面畸形，如小头畸形、下颌畸形和腭发育缺陷，以及一个导致发育性心脏和肾脏缺陷的基因座。对这些突变的杂合携带者的分析表明，这些基因座中很大一部分在杂合状态下表现出行为活动和感觉运动缺陷。这一发现支持对显性和隐性小鼠突变体进行系统的、相互的表型评估。除了提供模拟 6p 相关疾病的单基因突变体资源之外，这项工作还揭示了该区域意想不到的遗传复杂性。特别是，许多与 6p 缺失相关的表型可以通过多个基因之一的突变引起。这一发现意味着与连续基因缺失综合征相关的表型不仅可能是由于该区域中一个基因的剂量敏感性造成的，而且还可能是由于在同一生物过程中发挥作用的多个基因的单体性的综合效应造成的。
Monosomy of the human chromosome 6p terminal region results in a variety of congenital malformations that include brain, craniofacial, and organogenesis abnormalities. To examine the genetic basis of these phenotypes, we have carried out an unbiased functional analysis of the syntenic region of the mouse genome (proximal Mmu13). A genetic screen for recessive mutations in this region recovered thirteen lines with phenotypes relevant to a variety of clinical conditions. These include two loci that cause holoprosencephaly, two that underlie anophthalmia, one of which also contributes to other craniofacial abnormalities such as microcephaly, agnathia, and palatogenesis defects, and one locus responsible for developmental heart and kidney defects. Analysis of heterozygous carriers of these mutations shows that a high proportion of these loci manifest with behavioral activity and sensorimotor deficits in the heterozygous state. This finding argues for the systematic, reciprocal phenotypic assessment of dominant and recessive mouse mutants. In addition to providing a resource of single gene mutants that model 6p-associated disorders, the work reveals unsuspected genetic complexity at this region. In particular, many of the phenotypes associated with 6p deletions can be elicited by mutation in one of a number of genes. This finding implies that phenotypes associated with contiguous gene deletion syndromes can result not only from dosage sensitivity of one gene in the region but also from the combined effect of monosomy for multiple genes that function within the same biological process.