Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells.

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Abstract
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.