Winter H, Rogers M A, Mahr B, Cremer M, Krieg T, Navsaria H A, Leigh I M, Schweizer J
German Cancer Research Center, Heidelberg, Germany.
J Invest Dermatol. 1996 Mar;106(3):544-8. doi: 10.1111/1523-1747.ep12343976.
Mutations in distinct sites of epidermal keratins, in particular in the helix initiation and termination regions, cause human genodermatoses due to faulty intermediate filament formation. Extension of this observation to human hereditary hair and nail diseases includes population analyses of human hair keratin genes for natural sequence variations in the corresponding sites. Here we report on a large-scale genotyping of the short helix termination region (HTR) of the human type I cortical hair keratins hHa1, a3-I, and a3-II, and the cuticular hair keratin hHa2. We describe two polymorphic loci, P1 and P2, exclusively in the cuticular hHa2 gene, both creating dimorphic protein variants. P1 is due to a C to T mutation in a CpG element leading to a threonine to methionine substitution; P2 concerns a serine codon AGT that also occurs as an asparagine coding variant AAC. A third polymorphism, P3, is linked with a C to T point mutation located at the very beginning of intron 6. The three polymorphic sites are clustered in a 39-nucleotide sequence of the hHa2 gene. Both allelic frequency calculations in individuals of different races and pedigree studies indicate that the two-allelic hHa2 variants resulting from P1 and P2 occur ubiquitously in a ratio of about 1:1 (P1) and 2:1 (P2) respectively in our survey, and are clearly inherited as Mendelian traits. A genotype carrying both mutations simultaneously on one allele could not be detected in our sampling, and there was no association of a distinct allelic hHa2 variant with the known ethnic form variations of hairs. Sequence comparisons of the HTR of hHa2 with those of other type I hair keratins including the hHa2-ortholog from chimpanzee provide evidence that the P1- and P2-linked mutations must have occurred very early in human evolution and that the two P2-associated codon variants may be the result of two independent point mutations in an ancestral AGC serine codon. These data describe natural polymorphisms in the HTR of a member of the keratin multigene family.
表皮角蛋白不同位点的突变，尤其是螺旋起始和终止区域的突变，会因中间丝形成缺陷而导致人类遗传性皮肤病。将这一观察结果扩展到人类遗传性毛发和指甲疾病，包括对人类毛发角蛋白基因相应位点的自然序列变异进行群体分析。在此，我们报告了对人类I型皮质毛发角蛋白hHa1、a3-I和a3-II以及表皮毛发角蛋白hHa2的短螺旋终止区域（HTR）进行的大规模基因分型。我们描述了两个多态性位点，P1和P2，仅存在于表皮hHa2基因中，二者均产生双态蛋白变体。P1是由于CpG元件中的C到T突变，导致苏氨酸到甲硫氨酸的替换；P2涉及丝氨酸密码子AGT，它也作为天冬酰胺编码变体AAC出现。第三个多态性位点P3与位于内含子6起始处的C到T点突变相关。这三个多态性位点聚集在hHa2基因的一个39核苷酸序列中。对不同种族个体的等位基因频率计算以及系谱研究均表明，由P1和P2产生的双等位基因hHa2变体在我们的调查中普遍存在，比例分别约为1:1（P1）和2:1（P2），并且显然作为孟德尔性状遗传。在我们的样本中未检测到一个等位基因上同时携带这两种突变的基因型，并且没有发现特定的等位基因hHa2变体与已知的毛发种族形态变异之间存在关联。将hHa2的HTR与其他I型毛发角蛋白（包括来自黑猩猩的hHa2直系同源物）的HTR进行序列比较，结果表明与P1和P2相关的突变必定在人类进化的早期就已发生，并且两个与P2相关的密码子变体可能是祖先AGC丝氨酸密码子中两个独立点突变的结果。这些数据描述了角蛋白多基因家族一个成员的HTR中的自然多态性。
