Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome
Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome
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DOI：
10.1038/s41436-019-0445-x
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发表时间：
2019-09-01
影响因子：
8.8
通讯作者：
Isidor, Bertrand
中科院分区：
文献类型：
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作者：
Besnard, Thomas;Sloboda, Natacha;Isidor, Bertrand
目的：羊毛甾醇合成酶（LSS）基因最初在广泛先天性白内障家系中被发现。最近，一项研究强调了LSS与单纯性脑下垂体相关。我们将LSS的表型谱扩展到一种隐性神经外胚层综合征，以前称为脱发伴精神发育迟滞（APMR）综合征。它是一种罕见的常染色体隐性遗传疾病，其特征是低血糖和智力残疾（ID）或发育迟缓（DD），经常与早发性癫痫和其他皮肤病学features.Methods：通过多中心的国际合作研究，我们确定了LSS致病变异APMR个人无论是通过外显子组测序或LSS桑格测序。剪接缺陷进行了评估，转录本分析和minigene assay.Results：我们报告了10个APMR个人从6个无关的家庭与双等位基因变异LSS。我们还确定了一个受影响的个人与一个单一的罕见变异LSS和等位基因的不平衡，提示第二次事件。在鉴定的变体中，两个是截短的，七个是错义的，两个是剪接变体。结论：在胆固醇生物合成途径中，羊毛甾醇合成酶参与了（S）-2，3-氧化角鲨烯环化为羊毛甾醇的过程。我们的数据表明LSS作为一个主要基因引起一种罕见的隐性神经外胚层综合征。
Purpose: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features.Methods: Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay.Results: We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance.Conclusion: In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.