PLOS ONE2014-06-25 2:20 PM

胆固醇转运蛋白基因ABCA5突变会导致“多毛症” Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth


遗传性多毛症的罕见特征是非由雄激素刺激导致而表现出的毛发过度生长,且通常与额外先天性畸形相关联。在这项研究中,我们使用全外显子组测序在常染色体隐性遗传先天性全身多毛症实例(CGHT)(OMIM135400)中调查遗传缺陷。我们在在ABC脂质转运基因ABCA5的内含子32的5'供体剪接位点确定了单一碱基对的置换,这导致了病人整个毛囊中转运基因的异常剪接和蛋白水平降低。ABCA5的纯合隐性破坏导致溶酶体功能的降低,这导致自噬体及其携带物以及CGHT角质形成细胞中增多的内溶酶体胆固醇的积累。在某个与CGHT无关散发病例中,我们确定了1.3 Mb涵盖ABCA5的chr17q24.2-q24.3的神秘删除并发现病人整个毛囊中的ABCA5水平显着降低。总的来说,我们的研究结果支持了ABCA5作为构成CGHT表型的基因,并提出了一种先前未经确认的能调节毛发生长的新型作用。 


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. 


遗传性多毛症代表了毛发增生综合征的群体,这在人类群体中极为罕见。长久以来进化遗传学家对该返祖表型领域深受着迷。这些症状常伴随着包括骨骼,心脏和牙体缺损等的额外先天性畸形;因此识别构成该病理的机制和基因十分关键。复制数变量(CNVs中)先前已在555 kb包含四种基因的最小重叠区域的多例先天性全身多毛症中(CGHT)报道。然而,在这些或任何其他单个基因中的点突变都还未受描述来构成CGHT表型。在这项研究中,我们报道了ABC转运因子功能突变的首次丧失,ABCA5并确定了单独情况下位于最小共同区域内的额外复制数变量。我们在人类和小鼠毛囊上皮和间质分隔中发现了ABCA5的高水平表达,而在CGHT患者中这种表达则显著降低或完全丧失。ABCA5是一种溶酶体蛋白,且其功能丧失损害了溶酶体完整性并导致了胆固醇内溶酶体内部的蓄积。我们重要的研究结果证实了ABCA5在调节毛发生长中新的作用。

Author Summary 

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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