The retarded hair growth (rhg) mutation in mice is an allele of ornithine aminotransferase (Oat).
The retarded hair growth (rhg) mutation in mice is an allele of ornithine aminotransferase (Oat).
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DOI：
10.1016/j.ymgmr.2014.08.002
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发表时间：
2014
影响因子：
1.9
通讯作者：
King, Thomas R
中科院分区：
文献类型：
--
作者：
Bisaillon, Jason J;Radden, Legairre A 2nd;Szabo, Eric T;Hughes, Samantha R;Feliciano, Aaron M;Nesta, Alex V;Petrovic, Belinda;Palanza, Kenneth M;Lancinskas, Dainius;Szmurlo, Theodore A;Artus, David C;Kapper, Martin A;Mulrooney, James P;King, Thomas R
由于它们产生的表型相似，以及它们在7号染色体上的最接近报告位置，我们测试了隐性毛发生长迟缓(RHG)和卷曲(Fr)小鼠的等位基因，但发现这些缺陷是互补的。为了发现RHG的分子基础，我们分析了一个分离RHG的大型种内回交小组，并将该基因限制在0.9Mb区域，该区域包括不到10个基因，其中只有5个基因已被报道在皮肤中表达。RHG和成纤维细胞生长因子受体2的隐性零等位基因之间的互补测试排除了FGFR2作为毛发生长迟缓表型的可能基础，但对其中另一个候选基因鸟氨酸氨基转移酶(OAT)的DNA测序显示，与RHG等位基因特异相关的G到C颠倒，将导致基因产物第353位的甘氨酸到丙氨酸替换。为了测试这种错义突变是否可能导致突变表型，我们将RHG/RHG小鼠与携带燕麦隐性、围产期致死零突变(本文指定为燕麦Δ)的小鼠进行杂交。同时遗传RHG和燕麦Δ的杂交后代出生后生长和毛发发育明显延迟，表明这两个突变是等位基因，并强烈表明燕麦G到C突变与毛发生长迟缓表型有关。在+/+、+/rhG、rhG/rhG和rhG/燕麦Δ小鼠之间的比较表明，血浆鸟氨酸水平和鸟氨酸转氨酶活性(在肝脏裂解物中)符合这一分配。由于7个月和12个月龄的RHG/RHG和RHG/燕麦Δ视网膜的组织学显示脉络膜视网膜变性类似于先前描述的燕麦Δ/燕麦Δ小鼠的脉络膜视网膜变性，我们认为该突变体可能为人类脉络膜视网膜回旋性萎缩提供了一个理想的模型，在一些家庭中也是由甘氨酸353的替代引起的。基因图谱确定了小鼠RHG突变的少数候选基因。FGFR2和RHG的零等位基因之间的互补检测排除了等位基因。鸟氨酸氨基转移酶(OAT)的零等位基因不能补充RHG。RHG突变是燕麦中错义突变的结果。突变的RHG/RHG小鼠表现出燕麦功能减弱和脉络膜视网膜变性。
Because of the similar phenotypes they generate and their proximate reported locations on Chromosome 7, we tested the recessive retarded hair growth (rhg) and frizzy (fr) mouse mutations for allelism, but found instead that these defects complement. To discover the molecular basis of rhg, we analyzed a large intraspecific backcross panel that segregated for rhg and restricted this locus to a 0.9 Mb region that includes fewer than ten genes, only five of which have been reported to be expressed in skin. Complementation testing between rhg and a recessive null allele of fibroblast growth factor receptor 2 eliminated Fgfr2 as the possible basis of the retarded hair growth phenotype, but DNA sequencing of another of these candidates, ornithine aminotransferase (Oat), revealed a G to C transversion specifically associated with the rhg allele that would result in a glycine to alanine substitution at residue 353 of the gene product. To test whether this missense mutation might cause the mutant phenotype, we crossed rhg/rhg mice with mice that carried a recessive, perinatal-lethal, null mutation in Oat (designated OatΔ herein). Hybrid offspring that inherited both rhg and OatΔ displayed markedly delayed postnatal growth and hair development, indicating that these two mutations are allelic, and suggesting strongly that the G to C mutation in Oat is responsible for the retarded hair growth phenotype. Comparisons among +/+, +/rhg, rhg/rhg and rhg/OatΔ mice showed plasma ornithine levels and ornithine aminotransferase activities (in liver lysates) consistent with this assignment. Because histology of 7- and 12-month-old rhg/rhg and rhg/OatΔ retinas revealed chorioretinal degeneration similar to that described previously for OatΔ/OatΔ mice, we suggest that the rhg mutant may offer an ideal model for gyrate atrophy of the choroid and retina (GACR) in humans, which is also caused by the substitution of glycine 353 in some families. Genetic mapping identifies a small number of candidates for the mouse rhg mutation. Complementation testing between a null allele of Fgfr2 and rhg rules out allelism. A null allele of ornithine aminotransferase (Oat) fails to complement rhg. The rhg mutation results from a missense mutation in Oat. Mutant rhg/rhg mice show diminished OAT function, and chorioretinal degeneration.