Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa.
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.
Bandah-Rozenfeld
Dikla
D
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Collin
Rob W J
RW
Banin
Eyal
E
van den Born
L Ingeborgh
LI
Coene
Karlien L M
KL
Siemiatkowska
Anna M
AM
Zelinger
Lina
L
Khan
Muhammad I
MI
Lefeber
Dirk J
DJ
Erdinest
Inbar
I
Testa
Francesco
F
Simonelli
Francesca
F
Voesenek
Krysta
K
Blokland
Ellen A W
EA
Strom
Tim M
TM
Klaver
Caroline C W
CC
Qamar
Raheel
R
Banfi
Sandro
S
Cremers
Frans P M
FP
Sharon
Dror
D
den Hollander
Anneke I
AI
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
C412522:IMPG2 protein, human; D050505:Mutant Proteins; D011509:Proteoglycans