IDENTIFICATION OF GENETIC CAUSES OF NON SYNDROMIC RETINITIS PIGMENTOSA IN THE INDONESIAN POPULATION USING HIGH RESOLUTION HOMOZYGOSITY MAPPING

Abstract

Background : Retinitis Pigmentosa (RP) is an inherited disorder characterized by progressive periheral vision loss and night vision difficulties (nyctalopia) that can ultimately lead to central vission loss. Despite a broad knowledge on the genetic causes of RP, no study in Indonesia about the molecular genetics related to RP has been conducted yet. Objective: To identify the causative gene/loci of non-syndromic retinitis pigmentosa using high resolution homozygosity mapping, linkage analysis and DNA sequencing among Indonesian RP patients and also to determine the type of inheritance. Methods: The family molecular genetics study performed with thirty six patients and twenty nine relatives in sixteen families were involved. All affected patients were clinically evaluated. DNA samples of all affected individuals and their family members were collected in Indonesia. All affected DNA patients were analyzed for homozygous chromosomal regions by using either the Affymetrix 5.0 or the Illumina 6k SNP array. Known retinitis pigmentosa genes residing in the identified homozygous regions were analyzed by direct DNA sequencing to find mutations in gene that are associated with adRP and arRP. Results: The causative mutations were found in seven different families, a dominant missense change (c.403C>T; p.R135W) in the RHO gene, and recessive mutations in CRB1 (c.3914C>T; p.P1305L), ABCA4 (c.302+4A>C; altered splicing), NR2E3 (c.1025T>G; p.V342G), EYS (c.9082G>T; p.D3028Y), MERTK (c.2487-2A>G; altered splicing and complex rearrangement; p.G654AfsX41) and PDE6A (c.1675C>A; p.Y558X); and other candidate genes for sequencing such as FAM161A, ABCA4, RPE65, USH2A, PRCD. Conclusions: High resolution homozygosity mapping is an efficient gene mapping method applicable to rare recessive disorders. Significant homozygous regions which did not have any known gene can be used for identifying novel genes causative for RP. The high rate of solved families thus far indicates that the Indonesian population is extremely suitable to apply homozygosity mapping in a search for the genetic causes of recessive disorders. Key word: Retinitis Pigmentosa, autosomal dominant, autosomal recessive, non sydromic, homozygosity mapping, Indonesian