Functional Characterization of Splice Variants in the Diagnosis of Albinism

被引:2
|
作者
Diallo, Modibo [1 ]
Courdier, Cecile [1 ,2 ]
Mercier, Elina [1 ]
Sequeira, Angele [1 ]
Defay-Stinat, Alicia [1 ]
Plaisant, Claudio [2 ]
Mesdaghi, Shahram [3 ,4 ]
Rigden, Daniel [3 ]
Javerzat, Sophie [1 ]
Lasseaux, Eulalie [2 ]
Bourgeade, Laetitia [2 ]
Audebert-Bellanger, Severine [5 ]
Dollfus, Helene [6 ]
Hadj-Rabia, Smail [7 ]
Morice-Picard, Fanny [8 ]
Philibert, Manon [9 ]
Sidibe, Mohamed Kole [10 ]
Smirnov, Vasily [11 ]
Sylla, Ousmane [10 ]
Michaud, Vincent [1 ,2 ]
Arveiler, Benoit [1 ,2 ]
机构
[1] Bordeaux Univ, INSERM, Lab Malad Rares Genet & Metab, U1211, F-33076 Bordeaux, France
[2] Ctr Hosp Univ Bordeaux, Serv Genet Med, F-33076 Bordeaux, France
[3] Univ Liverpool, Inst Syst Mol & Integrat Biol, Liverpool L69 7ZB, England
[4] Univ Liverpool, Computat Biol Facil, MerseyBio, Crown St, Liverpool L69 7ZB, England
[5] Ctr Hosp Univ Brest, Serv Genet Med, F-29200 Brest, France
[6] Ctr Hosp Univ Strasbourg, Serv Genet Med, Strasbourg, France
[7] Hop Necker Enfants Malad, Serv Dermatol, F-75015 Paris, France
[8] Ctr Hosp Univ Bordeaux, Serv Dermatol, F-33076 Bordeaux, France
[9] Hop Fdn Rothschild, F-75019 Paris, France
[10] Infirm Hop Mil, BP 236, Bamako, Mali
[11] Ctr Hosp Univ Lille, Serv Explorat Fonct Vis & Neuroophtalmol, F-59037 Lille, France
关键词
albinism; splice variants; exon skipping; pseudoexon; RT-PCR; minigene assay; AMINO-ACID SUBSTITUTIONS; GENE; SERVER;
D O I
10.3390/ijms25168657
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Albinism is a genetically heterogeneous disease in which 21 genes are known so far. Its inheritance mode is autosomal recessive except for one X-linked form. The molecular analysis of exonic sequences of these genes allows for about a 70% diagnostic rate. About half (15%) of the unsolved cases are heterozygous for one pathogenic or probably pathogenic variant. Assuming that the missing variant may be located in non-coding regions, we performed sequencing for 122 such heterozygous patients of either the whole genome (27 patients) or our NGS panel (95 patients) that includes, in addition to all exons of the 21 genes, the introns and flanking sequences of five genes, TYR, OCA2, SLC45A2, GPR143 and HPS1. Rare variants (MAF < 0.01) in trans to the first variant were tested by RT-PCR and/or minigene assay. Of the 14 variants tested, nine caused either exon skipping or the inclusion of a pseudoexon, allowing for the diagnosis of 11 patients. This represents 9.8% (12/122) supplementary diagnosis for formerly unsolved patients and 75% (12/16) of those in whom the candidate variant was in trans to the first variant. Of note, one missense variant was demonstrated to cause skipping of the exon in which it is located, thus shedding new light on its pathogenic mechanism. Searching for non-coding variants and testing them for an effect on RNA splicing is warranted in order to increase the diagnostic rate.
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页数:22
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