A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice

脉络膜缺失 单倍型 遗传学 基因型 生物 外显子 表型 基因 生物信息学 医学
作者
Rocío Sánchez-Alcudia,Maria García‐Hoyos,Miguel Ángel López-Martínez,Noelia Sanchez-Bolivar,Olga Zurita,Ascensión Giménez,Cristina Villaverde,Luciana Rodrigues-Jacy da Silva,Marta Cortón,Raquel Pérez-Carro,Simona Torriano,Vasiliki Kalatzis,Carlo Rivolta,Almudena Ávila‐Fernández,Isabel Lorda,María José Trujillo-Tiebas,Blanca Garcı́a-Sandoval,María Isabel López-Molina,Fiona Blanco‐Kelly,Rosa Riveiro-Álvarez
出处
期刊:PLOS ONE [Public Library of Science]
卷期号:11 (4): e0151943-e0151943 被引量:45
标识
DOI:10.1371/journal.pone.0151943
摘要

Choroideremia (CHM) is a rare X-linked disease leading to progressive retinal degeneration resulting in blindness. The disorder is caused by mutations in the CHM gene encoding REP-1 protein, an essential component of the Rab geranylgeranyltransferase (GGTase) complex. In the present study, we evaluated a multi-technique analysis algorithm to describe the mutational spectrum identified in a large cohort of cases and further correlate CHM variants with phenotypic characteristics and biochemical defects of choroideremia patients. Molecular genetic testing led to the characterization of 36 out of 45 unrelated CHM families (80%), allowing the clinical reclassification of four CHM families. Haplotype reconstruction showed independent origins for the recurrent p.Arg293* and p.Lys178Argfs*5 mutations, suggesting the presence of hotspots in CHM, as well as the identification of two different unrelated events involving exon 9 deletion. No certain genotype-phenotype correlation could be established. Furthermore, all the patients´ fibroblasts analyzed presented significantly increased levels of unprenylated Rabs proteins compared to control cells; however, this was not related to the genotype. This research demonstrates the major potential of the algorithm proposed for diagnosis. Our data enhance the importance of establish a differential diagnosis with other retinal dystrophies, supporting the idea of an underestimated prevalence of choroideremia. Moreover, they suggested that the severity of the disorder cannot be exclusively explained by the genotype.
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