Novel Mutations in the MERTK Gene Are Responsible for Autosomal Recessive Rod-Cone Retinal Dystrophy in Two Families

Abstract

Purpose: : To report two novel mutations in the MERTK gene and the clinical phenotype seen in affected individuals from two families.

Methods: : 150 DNA samples from patients with LCA and autosomal recessive severe childhood onset rod cone dystrophy were analysed for mutations using a microarray (Asper-Ophthalmics LCA Chip). One subject was found to have a heterozygous variant in MERTK which was confirmed by direct sequencing; the second mutation identified by sequencing the remainder of the MERTK gene. Genome wide linkage analysis was performed using the Affymetrix 50K chip on members of a consanguineous family with recessive rod-cone dystrophy. Regions of homozygosity were identified in affected members. Candidate geneswere PCR amplified and sequenced. Identified mutations were confirmed by segregation analysis in the family and screening in ethnically matched controls.

Results: : Screening of LCA patients using the Asper LCA chip identified 1 patient with a known MERTK mutation. Sequencing of the rest of the gene identified a novel splice site mutation. This novel mutation was not found in 100 ECACC controls and segregated with disease. Genome wide scan in the consanguineous family found four regions of homozygosity. Screening of candidate genes identified a possible deletion of exon 8 in MERTK. Long range PCR identified a ~9kb deletion within MERTK removing exon 8 between two Alu repeats. The deletion segregated with disease. This deletion was not found in 100 controls. Each affected individual had a severe form of childhood onset rod-cone dystrophy.

Conclusions: : Mutations in MERTK are not a common cause of rod-cone retinal dystrophy. Non-homologous recombination between Alu Y repeats near or within MERTK may account for low identification of disease causing mutations to date as identification of such genomic rearrangements are difficult to identify with direct sequencing.

Keywords: mutations • degenerations/dystrophies • gene screening