Identification of two novel mutations in CDHR1 in consanguineous Spanish families with autosomal recessive retinal dystrophy

• Published in: Scientific reports Vol. 5; no. 1; p. 13902
• Main Authors: Nikopoulos, Konstantinos, Avila-Fernandez, Almudena, Corton, Marta, Lopez-Molina, Maria Isabel, Perez-Carro, Raquel, Bontadelli, Lara, Di Gioia, Silvio Alessandro, Zurita, Olga, Garcia-Sandoval, Blanca, Rivolta, Carlo, Ayuso, Carmen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-09-2015; Nature Publishing Group
• Subjects: 631/208; 692/308/2056; Acuity; Amino Acid Sequence; Amino Acid Substitution; Atrophy; Cadherins - chemistry; Cadherins - genetics; Case-Control Studies; Chromosome Mapping; Codons; Color vision; Consanguinity; DNA Mutational Analysis; DNA sequencing; Electroretinograms; Electroretinography; Etiology; European Continental Ancestry Group - genetics; Female; Fluorescein Angiography; Gene mapping; Genes, Recessive; Homozygote; Humanities and Social Sciences; Humans; Introns; Male; Molecular Sequence Data; mRNA; mRNA turnover; multidisciplinary; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Pedigree; Retina; Retinal degeneration; Retinal Dystrophies - diagnosis; Retinal Dystrophies - genetics; RNA Splice Sites; Science; Sequence Alignment; Spain; Spain
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep13902

Inherited retinal dystrophies present extensive phenotypic and genetic heterogeneity, posing a challenge for patients’ molecular and clinical diagnoses. In this study, we wanted to clinically characterize and investigate the molecular etiology of an atypical form of autosomal recessive retinal dystrophy in two consanguineous Spanish families. Affected members of the respective families exhibited an array of clinical features including reduced visual acuity, photophobia, defective color vision, reduced or absent ERG responses, macular atrophy and pigmentary deposits in the peripheral retina. Genetic investigation included autozygosity mapping coupled with exome sequencing in the first family, whereas autozygome-guided candidate gene screening was performed by means of Sanger DNA sequencing in the second family. Our approach revealed nucleotide changes in
CDHR1
; a homozygous missense variant (c.1720C > G, p.P574A) and a homozygous single base transition (c.1485 + 2T > C) affecting the canonical 5’ splice site of intron 13, respectively. Both changes co-segregated with the disease and were absent among cohorts of unrelated control individuals. To date, only five mutations in
CDHR1
have been identified, all resulting in premature stop codons leading to mRNA nonsense mediated decay. Our work reports two previously unidentified homozygous mutations in
CDHR1
further expanding the mutational spectrum of this gene.