ADRENOLEUKODYSTROPHY - EVIDENCE FOR X LINKAGE, INACTIVATION, AND SELECTION FAVORING THE MUTANT ALLELE IN HETEROZYGOUS CELLS
ADRENOLEUKODYSTROPHY - EVIDENCE FOR X LINKAGE, INACTIVATION, AND SELECTION FAVORING THE MUTANT ALLELE IN HETEROZYGOUS CELLS
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DOI：
10.1073/pnas.78.8.5066
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发表时间：
1981-01-01
期刊：
影响因子：
--
通讯作者：
NORUM, RA
中科院分区：
文献类型：
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作者：
MIGEON, BR;MOSER, HW;NORUM, RA
肾上腺脑白质营养不良（ALD）的男性皮肤成纤维细胞先前被证明是异常的C26脂肪酸含量。分析了分离这种突变的3个家庭的杂合子的皮肤成纤维细胞克隆，有2种类型：具有正常C26至C22脂肪酸比率的克隆和具有与受影响男性细胞中发现的类似的过量C26脂肪酸的克隆。该基因座明显为X连锁，易失活。在大多数的杂合子有显着更多的克隆异常类型比那些表达正常的等位基因，表明在体外增殖优势的突变型皮肤成纤维细胞。大多数杂合子血浆中脂肪酸水平的增加和1个家族中ALD和葡萄糖-6-磷酸脱氢酶（G6 PD）杂合子女性血细胞表型的增加证明了有利于突变等位基因的选择可能发生在体外，并可能解释为什么许多杂合子表现出疾病的临床症状。ALD和G6 PD基因座之间一定存在紧密连锁，因为在双杂合子母亲的18个信息后代中没有重组子。ALD基因座可以定位在人X染色体上Xq 28处的G6 PD基因座附近。
Skin fibroblasts of human males affected with adrenoleukodystrophy (ALD) were previously proven to be abnormal with respect to C26 fatty acid content. Skin fibroblast clones from heterozygotes in 3 families segregating this mutation were analyzed and were of 2 types: clones with normal ratios of C26 to C22 fatty acids and clones with an excess of C26 fatty acids similar to that found in cells of affected males. The locus is evidently X linked and subject to inactivation. In most of the heterozygotes there were significantly more clones of abnormal type than those expressing the normal allele, indicating a proliferative advantage in vitro for skin fibroblasts of mutant type. The increased levels of fatty acids in plasma in most heterozygotes and the phenotype of blood cells of women heterozygous for both ALD and glucose-6-phosphate dehydrogenase (G6PD) in 1 family are evidence that selection favoring the mutant allele may occur in vitro and may explain why many heterozygotes manifest clinical symptoms of the disease. There must be a close linkage between ALD and G6PD loci, because there are no recombinants among 18 informative offspring of doubly heterozygous mothers. The ALD locus can be mapped on the human X chromosome near the G6PD locus at Xq28.