Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.,Genetics in Medicine

当前位置： X-MOL 学术 › Genet. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2019-02-06 , DOI: 10.1038/s41436-019-0445-x
Thomas Besnard _{1,

2} , Natacha Sloboda ₃ , Alice Goldenberg ₄ , Sébastien Küry _{1,

2} , Benjamin Cogné _{1,

2} , Flora Breheret ₁ , Eva Trochu ₁ , Solène Conrad ₁ , Marie Vincent _{1,

2} , Wallid Deb _{1,

2} , Xavier Balguerie ₅ , Sébastien Barbarot ₆ , Geneviève Baujat ₇ , Tawfeg Ben-Omran ₈ , Anne-Claire Bursztejn ₉ , Virginie Carmignac _{10,

11} , Alexandre N Datta ₁₂ , Aline Delignières ₁₃ , Laurence Faivre _{10,

11} , Betty Gardie _{2,

14} , Jean-Louis Guéant ₃ , Paul Kuentz _{10,

11} , Marion Lenglet _{2,

14} , Marie-Cécile Nassogne ₁₅ , Vincent Ramaekers ₁₆ , Rhonda E Schnur ₁₇ , Yue Si ₁₇ , Erin Torti ₁₇ , Julien Thevenon ₁₈ , Pierre Vabres _{10,

11} , Lionel Van Maldergem _{19,

20} , Dorothea Wand ₂₁ , Arnaud Wiedemann ₃ , Bertrand Cariou ₂ , Richard Redon ₂ , Antonin Lamazière ₂₂ , Stéphane Bézieau _{1,

2} , Francois Feillet ₃ , Bertrand Isidor _{1,

2}

Affiliation

CHU de Nantes, Service de Génétique Médicale, Nantes, France.
L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU de Nantes, Nantes, France.
INSERM, UMR 1256 Nutrition-Genetics-Environmental Risk Exposure and Reference Centre of Inborn Metabolism Diseases, University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy), Nancy, France.
Department of Genetics, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
Department of Dermatology, University Hospital Center of Rouen, Rouen, France.
CHU de Nantes, Department of Dermatology, Nantes, France.
Department of Medical Genetics, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, IMAGINE Institute, Necker Enfants Malades Hospital, Paris, France.
Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
Dermatology department, hôpital Brabois, Vandœuvre-Lès, Vandœuvre-lès-Nancy, France.
Centre de Genetique et Centre de Reference Anomalies du Développement et Syndromes Malformatifs de l'Est, FHU-TRANSLAD, CHU Dijon, Dijon, France.
UMR-Inserm 1231 GAD Team, Genetique des Anomalies du Développement, Université de Bourgogne Franche-Comte, Dijon, France.
Department of Pediatric Neurology and Developmental Medicine, University of Basel Children's Hospital (UKBB), Basel, Switzerland.
CH Auray-Vannes, Hôpital Bretagne Atlantique, Service de Pediatrie, Vannes, France.
Ecole Pratique des Hautes Etudes, PSL Research University, Paris, France.
Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium.
Center of Autism and Department of Genetics, University Hospital Liege (CHU), Liège, Belgium.
GeneDx, 207 Perry Parkway, Gaithersburg, MD, USA.
Centre de Génétique, Hôpital Couple-Enfant, CHU de Grenoble-Alpes, La Tronche, France.
Centre de génétique humaine, Université de Franche-Comté, Besançon, France.
Integrative and Cognitive Neurosciences Research Unit EA481, University of Franche-Comté, Besançon, France.
Department Medical Genetic and Pathology, University Hospital of Basel (USB), Basel, Switzerland.
Laboratory of Mass Spectrometry, INSERM ERL 1157, CNRS UMR 7203 LBM, Sorbonne Universités-UPMC, CHU Saint-Antoine, Paris, France.

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.

中文翻译：

参与胆固醇生物合成的羊毛甾醇合酶基因 LSS 中的双等位基因致病变异导致智障脱发，这是一种罕见的隐性神经外胚层综合征。

目的羊毛甾醇合酶 (LSS) 基因最初是在患有广泛先天性白内障的家庭中描述的。最近，一项研究强调了与单纯性少毛症相关的 LSS。我们将 LSS 的表型谱扩展到一种隐性神经外胚层综合征，以前称为智力迟钝 (APMR) 综合征的脱发。它是一种罕见的常染色体隐性遗传病，以少毛症和智力障碍 (ID) 或发育迟缓 (DD) 为特征，通常与早发性癫痫和其他皮肤病学特征相关。方法通过一项多中心国际合作研究，我们通过外显子组测序或 LSS Sanger 测序鉴定了 APMR 个体的 LSS 致病变异。通过转录分析和小基因分析评估剪接缺陷。结果我们报告了来自 6 个不相关家族的 10 个 APMR 个体，在 LSS 中具有双等位基因变异。我们还确定了一个受影响的个体，该个体在 LSS 中有一个罕见的变体和一个等位基因失衡，表明第二个事件。在已识别的变体中，两个是截断变体，七个是错义变体，两个是剪接变体。胆固醇及其前体的量化并没有显示出明显的不平衡。结论在胆固醇生物合成途径中，羊毛甾醇合酶导致(S)-2,3-氧化角鲨烯环化为羊毛甾醇。我们的数据表明 LSS 是导致罕见的隐性神经外胚层综合征的主要基因。在已识别的变体中，两个是截断变体，七个是错义变体，两个是剪接变体。胆固醇及其前体的量化并没有显示出明显的不平衡。结论在胆固醇生物合成途径中，羊毛甾醇合酶导致(S)-2,3-氧化角鲨烯环化为羊毛甾醇。我们的数据表明 LSS 是导致罕见的隐性神经外胚层综合征的主要基因。在已识别的变体中，两个是截断变体，七个是错义变体，两个是剪接变体。胆固醇及其前体的量化并没有显示出明显的不平衡。结论在胆固醇生物合成途径中，羊毛甾醇合酶导致(S)-2,3-氧化角鲨烯环化为羊毛甾醇。我们的数据表明 LSS 是导致罕见的隐性神经外胚层综合征的主要基因。

更新日期：2019-02-06

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南