title: Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa.
abstract: Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases caused by progressive degeneration of the photoreceptor cells. Using autozygosity mapping, we identified two families, each with three affected siblings sharing large overlapping homozygous regions that harbored the IMPG2 gene on chromosome 3. Sequence analysis of IMPG2 in the two index cases revealed homozygous mutations cosegregating with the disease in the respective families: three affected siblings of Iraqi Jewish ancestry displayed a nonsense mutation, and a Dutch family displayed a 1.8 kb genomic deletion that removes exon 9 and results in the absence of seven amino acids in a conserved SEA domain of the IMPG2 protein. Transient transfection of COS-1 cells showed that a construct expressing the wild-type SEA domain is properly targeted to the plasma membrane, whereas the mutant lacking the seven amino acids appears to be retained in the endoplasmic reticulum. Mutation analysis in ten additional index cases that were of Dutch, Israeli, Italian, and Pakistani origin and had homozygous regions encompassing IMPG2 revealed five additional mutations; four nonsense mutations and one missense mutation affecting a highly conserved phenylalanine residue. Most patients with IMPG2 mutations showed an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity. The patient with the missense mutation, however, was diagnosed with maculopathy. The IMPG2 gene encodes the interphotoreceptor matrix proteoglycan IMPG2, which is a constituent of the interphotoreceptor matrix. Our data therefore show that mutations in a structural component of the interphotoreceptor matrix can cause arRP.
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Dikla
authors.initials: D
authors.lastname: Bandah-Rozenfeld
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.forename: Karlien L M
authors.initials: KL
authors.lastname: Coene
authors.forename: Anna M
authors.initials: AM
authors.lastname: Siemiatkowska
authors.forename: Lina
authors.initials: L
authors.lastname: Zelinger
authors.forename: Muhammad I
authors.initials: MI
authors.lastname: Khan
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Inbar
authors.initials: I
authors.lastname: Erdinest
authors.forename: Francesco
authors.initials: F
authors.lastname: Testa
authors.forename: Francesca
authors.initials: F
authors.lastname: Simonelli
authors.forename: Krysta
authors.initials: K
authors.lastname: Voesenek
authors.forename: Ellen A W
authors.initials: EA
authors.lastname: Blokland
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.forename: Sandro
authors.initials: S
authors.lastname: Banfi
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D002874:Chromosome Mapping; D020090:Chromosome Segregation / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005654:Fundus Oculi; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011509:Proteoglycans / Q000737:chemistry / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: C412522:IMPG2 protein, human; D050505:Mutant Proteins; D011509:Proteoglycans