{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T09:37:35Z","timestamp":1771493855284,"version":"3.50.1"},"reference-count":15,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T00:00:00Z","timestamp":1715299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Alopecia intellectual disability syndromes 4 (APMR4) caused by Lanosterol synthase (<jats:italic>LSS<\/jats:italic>) gene variants is a very rare autosomal recessive neuroectodermal syndrome. It is characterized by congenital alopecia and variable degrees of intellectual disability (ID), frequently associated with developmental delay (DD) and epilepsy. Currently, only three studies regarding <jats:italic>LSS<\/jats:italic>-related APMR4 have been reported, the pathogenesis of APMR4 is poorly understood. We studied one patient with <jats:italic>LSS<\/jats:italic>-related APMR4 who presented with severe intellectual disability, alopecia, early-onset epilepsy and developmental delay. She is absence of hair on the eyebrows, eyelashes, and scalp. Two novel <jats:italic>LSS<\/jats:italic> variants (c.401\u2009T\u2009&amp;gt;\u2009G and c.369C\u2009&amp;gt;\u2009G) were detected with whole-exome sequencing (WES). Analysis via WB experiment indicated that c.369\u2009&amp;gt;\u2009G reduced the protein expression level of <jats:italic>LSS<\/jats:italic>. Analysis of protein stability prediction showed a destabilizing for <jats:italic>LSS<\/jats:italic> caused by the variant c.401\u2009T\u2009&amp;gt;\u2009G. This study is the first study in Asia to date. These findings expanded the variantal spectrum of <jats:italic>LSS<\/jats:italic>-related APMR4 and revealed the potential pathogenic mechanism of <jats:italic>LSS<\/jats:italic> gene variants.<\/jats:p>","DOI":"10.3389\/fnins.2024.1301865","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T05:11:17Z","timestamp":1715317877000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Clinical and genetic analyses of APMR4 syndrome caused by novel biallelic LSS variants"],"prefix":"10.3389","volume":"18","author":[{"given":"Qingyun","family":"Kang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingwen","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haojiang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeshu","family":"Ning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liwen","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2025","DOI":"10.1038\/s41436-019-0445-x","article-title":"Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome","volume":"21","author":"Besnard","year":"2019","journal-title":"Genet. Med."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e1000598","DOI":"10.1371\/journal.pbio.1000598","article-title":"Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis","volume":"9","author":"Blanc","year":"2011","journal-title":"PLoS Biol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"3900","DOI":"10.1002\/ajmg.a.62438","article-title":"Four hypotrichosis families with mutations in the gene LSS presenting with and without neurodevelopmental phenotypes","volume":"185","author":"Cesarato","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1515\/jpem-2017-0101","article-title":"Congenital cataract with LSS gene mutations: a new case report","volume":"30","author":"Chen","year":"2017","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2242","DOI":"10.1007\/s12031-022-02074-y","article-title":"Expanding the phenotypic Spectrum of APMR4 syndrome caused by a novel variant in LSS gene and Review of literature","volume":"72","author":"Elaraby","year":"2022","journal-title":"J. Mol. Neurosci."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1111\/1346-8138.15697","article-title":"Novel mutations in Chinese hypotrichosis simplex patients associated with LSS gene","volume":"48","author":"Hua","year":"2021","journal-title":"J. Dermatol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/j.tips.2005.05.004","article-title":"Lord of the rings\u2014the mechanism foroxidosqualene:lanosterol cyclase becomes crystal clear","volume":"26","author":"Huff","year":"2005","journal-title":"Trends Pharmacol. Sci."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e07999","DOI":"10.7554\/eLife.07999","article-title":"Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways","volume":"26","author":"Mitsche","year":"2015","journal-title":"eLife"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1111\/ahg.12425","article-title":"Alopecia-mental retardation syndrome: molecular genetics of a rare neuro-dermal disorder","volume":"85","author":"Muzammal","year":"2021","journal-title":"Ann. Hum. Gen."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1007\/s00439-016-1756-5","article-title":"Association of AHSG with alopecia and mental retardation (APMR) syndrome","volume":"136","author":"Reza Sailani","year":"2017","journal-title":"Hum. Genet."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/j.ajhg.2018.09.011","article-title":"Bi-allelic mutations in LSS, encoding Lanosterol synthase, cause autosomal-recessive Hypotrichosis simplex","volume":"103","author":"Romano","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.bbrc.2004.01.052","article-title":"The monotopic membrane protein human oxidosqualene cyclase is active as monomer","volume":"315","author":"Ruf","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e1008628","DOI":"10.1371\/journal.pgen.1008628","article-title":"Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice","volume":"16","author":"Wada","year":"2020","journal-title":"PLoS Genet."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/nature14650","article-title":"Lanosterol reverses protein aggregation in cataracts","volume":"523","author":"Zhao","year":"2015","journal-title":"Nature"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2024.1301865\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T05:11:19Z","timestamp":1715317879000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2024.1301865\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,10]]},"references-count":15,"alternative-id":["10.3389\/fnins.2024.1301865"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2024.1301865","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,10]]},"article-number":"1301865"}}