Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone-rod dystrophy by pseudoexon activation

• Verfasst von: Weik, Anja Kathrin [VerfasserIn]
• Verfasst von: Rohrschneider, Klaus [VerfasserIn]
• Verfasst von: Strom, Tim M. [VerfasserIn]
• Verfasst von: Glöckle, Nicola [VerfasserIn]
• Verfasst von: Kohl, Susanne [VerfasserIn]
• Verfasst von: Wissinger, Bernd [VerfasserIn]
• Verfasst von: Weisschuh, Nicole [VerfasserIn]
• Titel: Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone-rod dystrophy by pseudoexon activation
• Verf.angabe: Anja K. Mayer, Klaus Rohrschneider, Tim M. Strom, Nicola Glöckle, Susanne Kohl, Bernd Wissinger and Nicole Weisschuh
• Jahr: 2016
• Jahr des Originals: 2015
• Umfang: 4 S.
• Fussnoten: Published: 08 July 2015 ; Gesehen am 13.05.2020
• Titel Quelle: Enthalten in: European journal of human genetics
• Ort Quelle: Basingstoke : Stockton Press, 1998
• Jahr Quelle: 2016
• Band/Heft Quelle: 24(2016), 3, Seite 459-462
• ISSN Quelle: 1476-5438
• DOI: doi:10.1038/ejhg.2015.144
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1698135777

Abstract

Several genes have been implicated in the autosomal recessive form of cone-rod dystrophy (CRD), but the majority of cases remain unsolved. We identified a homozygous interval comprising two known genes associated with the autosomal recessive form of CRD, namely RAB28 and PROM1, in a consanguineous family with clinical evidence of CRD. Both genes proved to be mutation negative upon sequencing of exons and canonical splice sites but whole-genome sequencing revealed a private variant located deep in intron 18 of PROM1. In silico and functional analyses of this variant using minigenes as splicing reporters revealed the integration of a pseudoexon in the mutant transcript, thereby leading to a premature termination codon and presumably resulting in a functional null allele. This is the first report of a deep intronic variant that acts as a splicing mutation in PROM1. The detection of such variants escapes the exon-focused techniques typically used in genetic analyses. Sequencing the entire genomic regions of known disease genes might identify more causal mutations in the autosomal recessive form of CRD.