在携带独特的c.6527insC突变的个体中,发现了罕见的皮肤疾病,隐性营养不良大疱性表皮松解症的西班牙血统起源。

IF 3.7 2区 医学 Q2 GENETICS & HEREDITY
Emily Mira Warshauer, Paul A Maier, Goran Runfeldt, Ignacia Fuentes, Maria José Escamez, Laura Valinotto, Monica Natale, Graciela Manzur, Nuria Illera, Marta Garcia, Marcela Del Rio, Angeles Mencia, Almudena Holguin, Fernando Larcher, Garrett Hellenthal, Adam R Brown, Liliana Consuegra, Carolina Rivera, Inês Nogueiro, Jean Tang, Anthony Oro, Peter Marinkovich, Francis Palisson, Matthias Titeux, Alain A Hovnanian, Eli Sprecher, Karl Skorecki, David Norris, Anna Bruckner, Igor Kogut, Ganna Bilousova, Dennis Roop
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The <i>COL7A1</i> c.6527insC mutation is curiously prevalent among individuals with RDEB and is found worldwide in Europe and the Americas. Previous research has suggested the possibility of a Sephardic Jewish origin of the mutation; however, individuals with RDEB are not known to have predominant Jewish ancestry.</p><p><strong>Methods: </strong>In this study, a global cohort of individuals with RDEB with the c.6527insC founder mutation from Spain, France, Argentina, Chile, Colombia and the USA were investigated by autosomal genotyping, pairwise identical-by-descent matching and a local ancestry analysis. 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引用次数: 0

摘要

背景:隐性营养不良大疱性表皮松解症(RDEB)是由VII型胶原蛋白基因(COL7A1)的功能缺失突变引起的一种罕见且严重的起泡性皮肤病。COL7A1 c.6527insC突变在RDEB患者中非常普遍,在欧洲和美洲都有发现。先前的研究表明,这种突变可能来自西班牙系犹太人;然而,患有RDEB的个体并不具有主要的犹太血统。方法:对来自西班牙、法国、阿根廷、智利、哥伦比亚和美国的c.6527insC始发突变RDEB患者进行常染色体基因分型、配对血统匹配和本地血统分析。进行年龄估计分析,以确定犹太创始人何时将c.6527insC突变引入伊比利亚和美洲原住民人群(分别为公元900年和1492年)。结果:在85%的个体中发现了跨越c.6527insC突变的单倍型西班牙系祖先,尽管在基因组的其他地方有混合祖先,并且没有已知的西班牙系祖先。该RDEB亚群与葡萄牙贝尔蒙特的一个已知的隐犹太人社区之间的血统匹配也被确定,为该RDEB亚群的隐犹太人祖先提供了支持。结论:这种由最普遍的c.6527insC突变统一的独特RDEB亚群的鉴定具有很大的潜力,可以利用CRISPR cas9基因和碱基编辑促进有希望的新的RDEB治疗。鉴定出一种允许对这种变体进行有效和安全编辑的单一向导RNA,将代表一种独特的药物,用于治疗具有相同创始突变的大量患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Sephardic origins revealed for rare skin disorder, recessive dystrophic epidermolysis bullosa, in individuals carrying the unique c.6527insC mutation.

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and severe blistering skin disorder caused by loss-of-function mutations in the type VII collagen gene (COL7A1). The COL7A1 c.6527insC mutation is curiously prevalent among individuals with RDEB and is found worldwide in Europe and the Americas. Previous research has suggested the possibility of a Sephardic Jewish origin of the mutation; however, individuals with RDEB are not known to have predominant Jewish ancestry.

Methods: In this study, a global cohort of individuals with RDEB with the c.6527insC founder mutation from Spain, France, Argentina, Chile, Colombia and the USA were investigated by autosomal genotyping, pairwise identical-by-descent matching and a local ancestry analysis. Age estimation analysis was performed to determine when Jewish founders introduced the c.6527insC mutation into Iberian and Native American populations (~900 CE and 1492 CE, respectively).

Results: Sephardic ancestry was identified at the haplotype spanning the c.6527insC mutation in 85% of the individuals, despite mixed ancestry elsewhere in the genome and no known recent Sephardic ancestry. Identical-by-descent matching between this RDEB subpopulation and a known crypto-Jewish community in Belmonte, Portugal was also ascertained, providing support for crypto-Jewish ancestry in this RDEB subpopulation.

Conclusion: The identification of this unique RDEB subpopulation unified by the single most prevalent c.6527insC mutation holds great potential to facilitate promising new RDEB therapies using CRISPR Cas 9 gene and base editing. The identification of a single guide RNA allowing efficient and safe editing of this variant would represent a unique drug to treat a large cohort of patients with the same founder mutation.

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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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