Dominant mutations in RP1L1 are responsible for occult macular dystrophy.
Occult macular dystrophy (OMD) is an inherited macular dystrophy characterized by progressive loss of macular function but normal ophthalmoscopic appearance. Typical OMD is characterized by a central cone dysfunction leading to a loss of vision despite normal ophthalmoscopic appearance, normal fluorescein angiography, and normal full-field electroretinogram (ERGs), but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly reduced at the central retina. Linkage analysis of two OMD families was performed by the SNP High Throughput Linkage analysis system (SNP HiTLink), localizing the disease locus to chromosome 8p22-p23. Among the 128 genes in the linkage region, 22 genes were expressed in the retina, and four candidate genes were selected. No mutations were found in the first three candidate genes, methionine sulfoxide reductase A (MSRA), GATA binding 4 (GATA4), and pericentriolar material 1 (PCM1). However, amino acid substitution of p.Arg45Trp in retinitis pigmentosa 1-like 1 (RP1L1) was found in three OMD families and p.Trp960Arg in a remaining OMD family. These two mutations were detected in all affected individuals but in none of the 876 controls. Immunohistochemistry of RP1L1 in the retina section of cynomolgus monkey revealed expression in the rod and cone photoreceptor, supporting a role of RP1L1 in the photoreceptors that, when disrupted by mutation, leads to OMD. Identification of RP1L1 mutations as causative for OMD has potentially broader implications for understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.
Akahori
Masakazu
M
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Meguro-ku, Japan.
Tsunoda
Kazushige
K
Miyake
Yozo
Y
Fukuda
Yoko
Y
Ishiura
Hiroyuki
H
Tsuji
Shoji
S
Usui
Tomoaki
T
Hatase
Tetsuhisa
T
Nakamura
Makoto
M
Ohde
Hisao
H
Itabashi
Takeshi
T
Okamoto
Haru
H
Takada
Yuichiro
Y
Iwata
Takeshi
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics*; D005190:Family; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D008040:Genetic Linkage; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012160:Retina / Q000473:pathology; D055815:Young Adult
D005136:Eye Proteins; C474032:RP1L1 protein, human
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