Pavan W J, Liddell R A, Wright A, Thibaudeau G, Matteson P G, McHugh K M, Siracusa L D
Laboratory for Genetic Disease Research, National Center for Human Genome Research, National Institutes of Health, Bethesda, Maryland 20892.
Mamm Genome. 1995 Jan;6(1):1-7. doi: 10.1007/BF00350885.
Mice homozygous for the lethal spotting (ls) mutation exhibit aganglionic megacolon and a white spotted coat owing to a lack of neural crest-derived enteric ganglia and melanocytes. The ls mutation disrupts the migration, differentiation, or survival of these neural crest lineages during mammalian development. A human congenital disorder, Hirschsprung disease (HSCR), is also characterized by aganglionic megacolon of the distal bowel and can be accompanied by hypopigmentation of the skin. HSCR has been attributed to multiple loci acting independently or in combination. The ls mouse serves as one animal model for HSCR, and the ls gene may represent one of the loci responsible for some cases of HSCR in humans. This study uses 753 N2 progeny from a combination of three intersubspecific backcrosses to define the molecular genetic linkage map of the ls region and to provide resources necessary for positional cloning. Similar to some cases of HSCR, the ls mutation acts semidominantly, its phenotypic effects dependent upon the presence of modifier genes segregating in the crosses. We have now localized the ls mutation to a 0.8-cM region between the D2Mit113 and D2Mit73/D2Mit174 loci. Three genes, endothelin-3 (Edn3), guanine nucleotide-binding protein alpha-stimulating polypeptide 1 (Gnas), and phosphoenolpyruvate carboxykinase (Pck1) were assessed as candidates for the ls mutation. Only Edn3 and Gnas did not recombine with the ls mutation. Mutational analysis of the Edn3 and Gnas genes will determine whether either gene is responsible for the neural crest deficiencies observed in ls/ls mice.
致死斑点（ls）突变的纯合子小鼠表现出无神经节性巨结肠和白色斑点皮毛，这是由于缺乏神经嵴衍生的肠神经节和黑素细胞所致。ls突变在哺乳动物发育过程中破坏了这些神经嵴谱系的迁移、分化或存活。一种人类先天性疾病，先天性巨结肠（HSCR），其特征也是远端肠道无神经节性巨结肠，并且可能伴有皮肤色素减退。HSCR归因于多个独立或联合作用的基因座。ls小鼠作为HSCR的一种动物模型，ls基因可能代表人类某些HSCR病例的相关基因座之一。本研究使用来自三个亚种间回交组合的753只N2后代来确定ls区域的分子遗传连锁图谱，并提供定位克隆所需的资源。与某些HSCR病例类似，ls突变呈半显性作用，其表型效应取决于杂交中分离的修饰基因的存在。我们现已将ls突变定位到D2Mit113和D2Mit73/D2Mit174基因座之间的0.8厘摩区域。评估了三个基因，即内皮素-3（Edn3）、鸟嘌呤核苷酸结合蛋白α刺激多肽1（Gnas）和磷酸烯醇丙酮酸羧激酶（Pck1）作为ls突变的候选基因。只有Edn3和Gnas与ls突变没有重组。对Edn3和Gnas基因的突变分析将确定这两个基因是否是导致ls/ls小鼠中观察到的神经嵴缺陷的原因。
