Author: Chu, Man-yu
Title: Mutational analysis of the RLBP1 and CHM genes in Hong Kong Chinese patients with retinal degeneration
Degree: M.Sc.
Year: 2003
Subject: Hong Kong Polytechnic University -- Dissertations
Retinitis pigmentosa
Retinal degeneration
Eye -- Diseases -- Genetic aspects
Department: Multi-disciplinary Studies
School of Nursing
Pages: xiii, 126 leaves : ill. (some col.) ; 30 cm
Language: English
Abstract: The RLBP1 gene is one of the causative genes for retinitis pigmentosa (RP) and the CHM gene is the only causative gene for choroideremia (CHM). Both diseases are inherited retinal degenerative diseases. RP is the term applied to a clinically and genetically heterogeneous group of retinal degenerative diseases. Its prevalence has been estimated to be 1:3000-1:5000. The RLBP1 gene, located on chromosome 15q26, consists of 8 exons and 7 introns. The gene encodes a protein called retinaldehyde binding protein-1 (RLBP1) which is abundant in the retinal pigment epithelium (RPE) and the Muller cells of the neuroretina, where it carries 11-cis-retinol and 11-cis-retinaldehyde. CHM is an X-Iinked retinal degenerative disorder resulting from the absence of functional Rab escort protein 1 (REP-1). The CHM gene consists of 15 exons and 14 introns. In this study, mutational analysis of the RLBP1 and the CHM genes was carried out for a group of Hong Kong Chinese patients with RP or CHM. The samples were collected from patients of the Hong Kong Patients Register of Retinal Degenerations, a territorial register with clinical and genetic information of patients with inherited retinal degenerative diseases. The RLBP1 gene is associated with autosomal recessive retinitis pigmentosa and only a few mutations have been found in this gene. Mutational analysis of the CHM gene was carried out for 5 families diagnosed as CHM. Denaturing high performance liquid chromatography (DHPLC) was used for mutation screening. All exons and their flanking intervening sequences (IVS) were amplified by polymerase chain reaction. One or two test amplified products were mixed and denatured together with that of a control sample, and then subjected to mutation analysis. Several mutations and polymorphisms were found in the RLBP1 and CHM genes. This study identified the 222G->A transition mutation in 5' untranslated region (UTR) (5' UTR-70G>A), the 1412G->T transversion mutation in 3' UTR region (3' UTR+167G>T, 3' UTR+296G>A), IVS6+20C>T transition mutation, IVS6+110G>A transition mutation, IVS2-35_-36insT, 482G->A transition mutation causing Arg64Gln, and 597A->C transversion mutation leading to a silent mutation in the RLBP1 gene. Several polymorphisms were published previously. However, no disease -causing mutation of the RLBP1 gene was found in this study. A single nucleotide polymorphism was also found in intron 2 of the CHM gene (IVS2+80C>T). Five mutations were found in 5 CHM families, each with one distinct mutation. One family was found to have an insertion A in exon 5 (657_658insA) with the result of a sequence frameshift leading to a truncated protein of 221 amino acids in length. The second family was found to have a 4 bp deletion in exon 5 (682_685delTCAC) with a sequence frameshift leading to a truncated protein of 229 amino acids in length. A splice site mutation was found in the third family in intron 5 (IVS5-1G>C) and expected to produce splicing error. A transversion C->A mutation at position 1049 in exon 8 of a family caused a nonsense mutation Ser340Stop (S340X) which was first found in a Spanish family. The fifth family was found to have a 4 bp deletion in exon 13 (1614_ 16l7delTGTT) with a sequence frameshift resulting in a truncated protein of 534 amino acids in length. The CHM gene has been shown previously to have a variety of mutational spots and two novel findings (657_ 658insA and IVS5-lG>C) were found in this study. None of the mutations was present in a panel of at least 98 control subjects, thus making it unlikely that the identified nucleotide changes were polymorphisms present in the normal population.
Rights: All rights reserved
Access: restricted access

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