Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice
Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice
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DOI：
10.1371/journal.pgen.1008628
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发表时间：
2020-02-01
期刊：
影响因子：
4.5
通讯作者：
Kure, Shigeo
中科院分区：
文献类型：
--
作者：
Wada, Yoichi;Kikuchi, Atsuo;Kure, Shigeo
皮肤损伤、白内障和先天性异常通常与合成胆固醇的酶的遗传缺陷有关。羊毛甾醇合成酶（LSS）在胆固醇生物合成途径中将(S)-2,3-环氧喹啉转化为羊毛甾醇。先天性白内障家族中有LSS双等位基因突变的报道，最近在毛少症病例中也有报道。然而，这些表型是否由每个组织中的LSS酶缺陷引起尚不清楚，并且体内LSS酶活性的破坏尚未得到验证。我们确定了两例具有新型双等位LSS突变的患者，他们表现出先天性毛少和中线异常，但没有白内障。我们通过测量前额皮脂中(S)-2,3-环氧喹啉/羊毛甾醇的比值发现LSS酶反应在患者中发生阻断，这将是诊断LSS缺乏症的一个很好的生物标志物。表皮特异性Lss敲除小鼠表现出新生儿因脱水致死，表明Lss可能参与皮肤屏障完整性。他莫昔芬诱导的表皮Lss敲除引起成年小鼠毛少症。晶状体特异性Lss基因敲除小鼠患有白内障。这些结果证实，由于LSS在每个组织中的功能缺失突变，LSS缺乏症导致毛少症和白内障。这些小鼠模型将有助于阐明与LSS紊乱相关的病理生理机制，并有助于开发LSS缺陷的治疗方法。皮肤病变、白内障和先天性异常经常与遗传性胆固醇合成酶缺乏有关。LSS编码羊毛甾醇合成酶，这是胆固醇生物合成途径中的一种酶，在先天性白内障和毛少症的家族中，LSS的双等位基因突变已被报道。然而，这些表型是否由每个组织中的LSS酶缺乏引起尚不清楚，并且体内LSS酶活性的破坏尚未得到验证。我们通过测量前额皮脂中LSS酶的代谢物，发现双等位基因LSS突变和先天性毛少症患者体内LSS代谢抑制，这将是诊断LSS缺乏症的良好生物标志物。我们通过创建组织特异性Lss敲除小鼠再现了毛少症和白内障。我们的小鼠研究证实，由于LSS在每个组织中的功能突变丧失，LSS缺乏症导致毛少症和白内障。这些小鼠将导致与LSS中断相关的病理生理机制的阐明，并为LSS缺陷的治疗方法的发展提供帮助。
Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.Author summary Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies of cholesterol synthetic enzymes. LSS encodes lanosterol synthase, an enzyme in the cholesterol biosynthesis pathway, and biallelic mutations in LSS have been reported in families with congenital cataracts and hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiency in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We showed that LSS metabolic inhibition in patients with biallelic LSS mutations and congenital hypotrichosis in vivo by measuring metabolites of the LSS enzyme in the forehead sebum, which would be good biomarkers for the diagnosis of LSS deficiency. We recapitulated hypotrichosis and cataracts by creating tissue-specific Lss knockout mice. Our mouse studies confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mice will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.