Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex
Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex
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DOI：
10.1016/j.ajhg.2018.09.011
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发表时间：
2018-11-01
影响因子：
9.8
通讯作者：
Betz, Regina C.
中科院分区：
文献类型：
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作者：
Romano, Maria-Teresa;Tafazzoli, Aylar;Betz, Regina C.
单纯性少毛症 (HS) 是一种罕见的遗传性脱发，其特征是儿童时期开始出现弥漫性、进行性头皮和身体脱发。尽管研究已确定了许多致病基因，但约 50% 的热射病病例的遗传病因学仍不清楚。本报告描述了通过全外显子组测序对三个不相关的患有无法解释的、可能是常染色体隐性 HS 的家族中 LSS 基因的五种不同突变进行的鉴定。受影响的个体表现出稀疏或缺失的胎毛状头皮毛发、稀疏且脆弱的眉毛、以及稀疏的睫毛和体毛。 LSS 编码羊毛甾醇合酶 (LSS)，它是胆固醇生物合成途径中的关键酶。该途径在毛囊生物学中发挥着重要作用。将 LSS 蛋白表达定位于毛干和毛囊球后，使用免疫印迹和免疫荧光分析突变对角质形成细胞的影响。有趣的是，野生型 LSS 定位于内质网 (ER)，而突变型 LSS 蛋白则部分定位于 ER 之外。一个似乎合理的假设是，这种错误定位对毛囊细胞具有潜在的有害影响。免疫印迹显示野生型和突变蛋白的总体水平没有差异。对血液胆固醇水平的分析显示胆固醇或胆固醇中间体没有减少，从而支持了先前提出的替代胆固醇途径的假设。 LSS 被鉴定为常染色体隐性 HS 的致病基因，凸显了胆固醇途径在毛囊生物学中的重要性，并可能促进一般脱发疾病的新治疗方法。
Hypotrichosis simplex (HS) is a rare form of hereditary alopecia characterized by childhood onset of diffuse and progressive scalp and body hair loss. Although research has identified a number of causal genes, genetic etiology in about 50% of HS cases remains unknown. The present report describes the identification via whole-exome sequencing of five different mutations in the gene LSS in three unrelated families with unexplained, potentially autosomal-recessive HS. Affected individuals showed sparse to absent lanugo-like scalp hair, sparse and brittle eyebrows, and sparse eyelashes and body hair. LSS encodes lanosterol synthase (LSS), which is a key enzyme in the cholesterol biosynthetic pathway. This pathway plays an important role in hair follicle biology. After localizing LSS protein expression in the hair shaft and bulb of the hair follicle, the impact of the mutations on keratinocytes was analyzed using immunoblotting and immunofluorescence. Interestingly, wild-type LSS was localized in the endoplasmic reticulum (ER), whereas mutant LSS proteins were localized in part outside of the ER. A plausible hypothesis is that this mislocalization has potential deleterious implications for hair follicle cells. Immunoblotting revealed no differences in the overall level of wild-type and mutant protein. Analyses of blood cholesterol levels revealed no decrease in cholesterol or cholesterol intermediates, thus supporting the previously proposed hypothesis of an alternative cholesterol pathway. The identification of LSS as causal gene for autosomal-recessive HS highlights the importance of the cholesterol pathway in hair follicle biology and may facilitate novel therapeutic approaches for hair loss disorders in general.