Autosomal-Dominant Woolly Hair Resulting from Disruption of Keratin 74 (KRT74), a Potential Determinant of Human Hair Texture
Autosomal-Dominant Woolly Hair Resulting from Disruption of Keratin 74 (KRT74), a Potential Determinant of Human Hair Texture
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DOI：
10.1016/j.ajhg.2010.02.025
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发表时间：
2010-04-09
影响因子：
9.8
通讯作者：
Christiano, Angela M.
中科院分区：
文献类型：
--
作者：
Shimomura, Yutaka;Wajid, Muhammad;Christiano, Angela M.
常染色体显性羊毛状毛（ADWH）是一种罕见的疾病，其特征是头发紧密卷曲。ADWH的分子基础以前没有报道过。在这项研究中，我们确定了一个巴基斯坦家庭与ADWH。该家系与染色体12 q12-q14.1连锁，含有II型角蛋白基因簇。我们在所有受影响的家族成员中发现了角蛋白74（KR 7 '74）基因螺旋起始基序内的杂合突变p.Asn148Lys。KRT 74编码内根鞘（IRS）特异性上皮（软）角蛋白74。我们证明，突变K74蛋白的结果在培养细胞中的角蛋白中间丝的形成中断，最有可能在显性负的方式。此外，我们测序了小鼠Krt 71 -74基因中的显性Caracul样4（Ca 14）等位基因，其特征在于波浪形外套表型，并映射到小鼠染色体15的相同区域作为Caracul（Ca）和减少外套（Rco）等位基因。我们发现了一个杂合突变，p.Glu440Lys，而不是在Krt 74，但在相邻的基因，Krt 71。Krt 71先前被报道含有Ca和Rco突变，以及与卷毛犬相关的编码SNP。在这项研究中，我们定义了ADWH表型导致突变的毛囊特异性上皮角蛋白在人类。我们的研究结果不仅进一步强调了IRS特异性上皮角蛋白基因Krt 71 -74在毛发疾病中的关键作用，而且还打开了这些基因可能作为哺乳动物物种毛发纹理正常变异的遗传决定因素的可能性。
Autosomal-dominant woolly hair (ADWH) is a rare disorder characterized by tightly curled hair. The molecular basis of ADWH has not previously been reported. In this study, we identified a Pakistani family with ADWH. The family showed linkage to chromosome 12q12-q14.1, containing the type II keratin gene cluster. We discovered a heterozygous mutation, p.Asn148Lys, within the helix initiation motif of the keratin 74 (KR7'74) gene in all affected family members. KRT74 encodes the inner root sheath (IRS)-specific epithelial (soft) keratin 74. We demonstrate that the mutant K74 protein results in disruption of keratin intermediate filament formation in cultured cells, most likely in a dominant-negative manner. Furthermore, we sequenced the mouse Krt71-74 genes in the dominant Caracul-like 4 (Ca14) allele, which is characterized by a wavy-coat phenotype and maps to the same region of mouse chromosome 15 as the Caracul (Ca) and Reduced coat (Rco) alleles. We identified a heterozygous mutation, p.Glu440Lys, not in Krt74 but in the neighboring gene, Krt71. Krt71 was previously reported to harbor Ca and Rco mutations, as well as a coding SNP that is associated with curly-coated dogs. In this study, we define the ADWH phenotype resulting from a mutation in a hair-follicle-specific epithelial keratin in humans. Our findings not only further underscore the crucial roles of the IRS-specific epithelial keratin genes Krt71-74 in hair disorders but also open the possibility that these genes might function as genetic determinants of normal variation in hair texture across mammalian species.