학술논문
Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome
Document Type
Original Paper
Author
Besnard, Thomas; Sloboda, Natacha; Goldenberg, Alice; Küry, Sébastien; Cogné, Benjamin; Breheret, Flora; Trochu, Eva; Conrad, Solène; Vincent, Marie; Deb, Wallid; Balguerie, Xavier; Barbarot, Sébastien; Baujat, Geneviève; Ben-Omran, Tawfeg; Bursztejn, Anne-Claire; Carmignac, Virginie; Datta, Alexandre N.; Delignières, Aline; Faivre, Laurence; Gardie, Betty; Guéant, Jean-Louis; Kuentz, Paul; Lenglet, Marion; Nassogne, Marie-Cécile; Ramaekers, Vincent; Schnur, Rhonda E.; Si, Yue; Torti, Erin; Thevenon, Julien; Vabres, Pierre; Van Maldergem, Lionel; Wand, Dorothea; Wiedemann, Arnaud; Cariou, Bertrand; Redon, Richard; Lamazière, Antonin; Bézieau, Stéphane; Feillet, Francois; Isidor, Bertrand
Source
Genetics in Medicine: Official journal of the American College of Medical Genetics and Genomics. 21(9):2025-2035
Subject
Language
English
ISSN
1098-3600
1530-0366
1530-0366
Abstract
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.