Mutations in the cholesterol transporter gene ABCA5 are associated with excessive hair overgrowth.
Mutations in the cholesterol transporter gene ABCA5 are associated with excessive hair overgrowth.
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DOI：
10.1371/journal.pgen.1004333
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发表时间：
2014
期刊：
影响因子：
4.5
通讯作者：
Christiano AM
中科院分区：
文献类型：
--
作者：
DeStefano GM;Kurban M;Anyane-Yeboa K;Dall'Armi C;Di Paolo G;Feenstra H;Silverberg N;Rohena L;López-Cepeda LD;Jobanputra V;Fantauzzo KA;Kiuru M;Tadin-Strapps M;Sobrino A;Vitebsky A;Warburton D;Levy B;Salas-Alanis JC;Christiano AM
遗传性多毛症是一种罕见的综合征，其特征是毛发过度生长，而不是由雄激素刺激引起的，通常与其他先天性异常有关。在这项研究中，我们使用全外显子组测序研究了常染色体隐性先天性广泛性终末多毛症（CGHT） （OMIM135400）的遗传缺陷。我们在ABC脂质转运基因ABCA5的内含子32的5 '供体剪接位点发现了一个单碱基对替换，导致转录物剪接异常，并在整个患者毛囊中降低蛋白质水平。ABCA5的纯合子隐性破坏导致溶酶体功能降低，从而导致CGHT角化细胞中自噬体、自噬体货物的积累以及内溶酶体胆固醇的增加。在一个不相关的散发性CGHT病例中，我们发现了包含ABCA5的chr17q24.2-q24.3的1.3 Mb隐性缺失，并发现ABCA5水平在整个患者毛囊中显着降低。总的来说，我们的研究结果支持ABCA5作为CGHT表型的基因，并表明该基因在调节头发生长方面具有一种新的，以前未被认识到的作用。遗传性多毛病代表了一组在人类中极为罕见的毛发过度生长综合征，由于它们被认为是祖先表型的复发，因此一直是进化遗传学家非常感兴趣的领域。这些综合征通常伴有额外的先天性异常，包括骨骼、心脏和牙齿缺陷；因此，确定病理机制和基因是至关重要的。拷贝数变异（CNVs）先前已在几例先天性广泛性终末多毛症（CGHT）中报道，其最小重叠区域为555kb，包含四个基因。然而，在这些或任何其他单一基因中没有点突变被描述为CGHT表型的基础。在这项研究中，我们报告了ABC转运体ABCA5的第一个功能缺失突变，并在最小共同区域的另一个单独病例中发现了一个额外的拷贝数变异。我们发现ABCA5在人和小鼠毛囊的上皮和间充质区室中都有高水平的表达，而在CGHT患者中，这种表达显著降低或完全丧失。ABCA5是一种溶酶体蛋白，它的功能丧失会损害溶酶体的完整性，并导致内溶酶体内胆固醇的积累。重要的是，我们的发现支持了ABCA5在调节头发生长中的新作用。
Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5′ donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth. Inherited hypertrichoses represent a group of hair overgrowth syndromes that are extremely rare in humans and have remained an area of great interest to evolutionary geneticists since they are considered to be recurrences of an ancestral phenotype. These syndromes often present with additional congenital abnormalities including bone, heart and dental defects; thus, it is crucial to identify the mechanisms and genes underlying the pathology. Copy number variants (CNVs) have previously been reported in several cases of congenital generalized hypertrichosis terminalis (CGHT) with a minimal overlapping region of 555 kb encompassing four genes. However, no point mutations in these or any other single genes have been described to underlie the CGHT phenotype. In this study, we report the first loss-of-function mutation in an ABC transporter, ABCA5 and identified an additional copy number variant in a separate case that lies within the minimal common region. We found high levels of ABCA5 expression in both epithelial and mesenchymal compartments of human and mouse hair follicles, and in CGHT patients, this expression is significantly reduced or completely lost. ABCA5 is a lysosomal protein, and its loss-of-function compromises the integrity of lysosomes and leads to an intra-endolysosomal accumulation of cholesterol. Importantly, our findings support a novel role for ABCA5 in regulating hair growth.
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影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
影响因子：
2.2
作者：
Helmerl, Susanne;Bosserhoff, Anja K.;Schmitz, Gerd
通讯作者：
Schmitz, Gerd
在没有刺猬信号的情况下，头发发育异常和明显的卵泡转化向乳腺。
影响因子：
11.8
作者：
Gritli-Linde, Amel;Hallberg, Kristina;Harfe, Brian D.;Reyahi, Azadeh;Kannius-Janson, Marie;Nilsson, Jeanette;Cobourne, Martyn T.;Sharpe, Paul T.;McMahon, Andrew P.;Linde, Anders
通讯作者：
Linde, Anders
影响因子：
--
作者：
BEIGHTON, P
通讯作者：
BEIGHTON, P
影响因子：
4.6
作者：
Chi, Woo;Wu, Eleanor;Morgan, Bruce A.
通讯作者：
Morgan, Bruce A.