{"title":"一个 1 型眼性白化病家族的 TYR 基因上游区域存在 65 千碱基缺失。","authors":"Modibo Diallo , Alicia Defay-Stinat , Victor Gindensperger , Angèle Sequeira , Aurélien Trimouille , Sophie Javerzat , Laetitia Bourgeade , Claudio Plaisant , Eulalie Lasseaux , Vincent Michaud , Isabelle Drumare , Benoit Arveiler","doi":"10.1016/j.gene.2024.149079","DOIUrl":null,"url":null,"abstract":"<div><div>Oculocutaneous albinism type 1 is caused by variants in the <em>TYR</em> (<em>tyrosinase</em>) gene. We describe a family with two affected sibs who inherited the pathogenic missense <em>TYR</em> variant c.1146C > A;p.(Asn382Lys) from their mother and a deletion encompassing 65 kilobase pairs of the upstream region of the gene between hg38 coordinates chr11:89110944 and chr11:89175770, from their father. The deletion likely arose by non-homologous recombination since the regions including the two deletion breakpoints share no sequence homology. The deletion contains a single enhancer element that is homologous to a 5′ <em>Tyr</em> core regulatory element in the mouse. A luciferase reporter assay showed that this element had a positive regulatory activity. This represents to our knowledge the first deletion solely restricted to non-coding upstream sequences of the <em>TYR</em> gene. It is assumed that the deletion down-regulates expression of the <em>TYR</em> gene and is therefore pathogenic, allowing to establish the diagnosis of OCA 1 in the patients. This study underscores the need to extend the search for pathogenic variants to regulatory regions either by whole genome sequencing or by targeted next generation sequencing of a panel including entire genes (exons, introns, flanking sequences) in order to improve the diagnostic rate in patients with albinism.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"935 ","pages":"Article 149079"},"PeriodicalIF":2.6000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A 65 kilobase deletion of the upstream TYR gene region in a family with oculocutaneous albinism type 1\",\"authors\":\"Modibo Diallo , Alicia Defay-Stinat , Victor Gindensperger , Angèle Sequeira , Aurélien Trimouille , Sophie Javerzat , Laetitia Bourgeade , Claudio Plaisant , Eulalie Lasseaux , Vincent Michaud , Isabelle Drumare , Benoit Arveiler\",\"doi\":\"10.1016/j.gene.2024.149079\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Oculocutaneous albinism type 1 is caused by variants in the <em>TYR</em> (<em>tyrosinase</em>) gene. We describe a family with two affected sibs who inherited the pathogenic missense <em>TYR</em> variant c.1146C > A;p.(Asn382Lys) from their mother and a deletion encompassing 65 kilobase pairs of the upstream region of the gene between hg38 coordinates chr11:89110944 and chr11:89175770, from their father. The deletion likely arose by non-homologous recombination since the regions including the two deletion breakpoints share no sequence homology. The deletion contains a single enhancer element that is homologous to a 5′ <em>Tyr</em> core regulatory element in the mouse. A luciferase reporter assay showed that this element had a positive regulatory activity. This represents to our knowledge the first deletion solely restricted to non-coding upstream sequences of the <em>TYR</em> gene. It is assumed that the deletion down-regulates expression of the <em>TYR</em> gene and is therefore pathogenic, allowing to establish the diagnosis of OCA 1 in the patients. This study underscores the need to extend the search for pathogenic variants to regulatory regions either by whole genome sequencing or by targeted next generation sequencing of a panel including entire genes (exons, introns, flanking sequences) in order to improve the diagnostic rate in patients with albinism.</div></div>\",\"PeriodicalId\":12499,\"journal\":{\"name\":\"Gene\",\"volume\":\"935 \",\"pages\":\"Article 149079\"},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2024-11-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Gene\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0378111924009600\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gene","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0378111924009600","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
A 65 kilobase deletion of the upstream TYR gene region in a family with oculocutaneous albinism type 1
Oculocutaneous albinism type 1 is caused by variants in the TYR (tyrosinase) gene. We describe a family with two affected sibs who inherited the pathogenic missense TYR variant c.1146C > A;p.(Asn382Lys) from their mother and a deletion encompassing 65 kilobase pairs of the upstream region of the gene between hg38 coordinates chr11:89110944 and chr11:89175770, from their father. The deletion likely arose by non-homologous recombination since the regions including the two deletion breakpoints share no sequence homology. The deletion contains a single enhancer element that is homologous to a 5′ Tyr core regulatory element in the mouse. A luciferase reporter assay showed that this element had a positive regulatory activity. This represents to our knowledge the first deletion solely restricted to non-coding upstream sequences of the TYR gene. It is assumed that the deletion down-regulates expression of the TYR gene and is therefore pathogenic, allowing to establish the diagnosis of OCA 1 in the patients. This study underscores the need to extend the search for pathogenic variants to regulatory regions either by whole genome sequencing or by targeted next generation sequencing of a panel including entire genes (exons, introns, flanking sequences) in order to improve the diagnostic rate in patients with albinism.
期刊介绍:
Gene publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses.