Novel RP1L1 Variants and Genotype-Photoreceptor Microstructural Phenotype Associations in Cohort of Japanese Patients With Occult Macular Dystrophy.
OBJECTIVE
To determine the clinical and genetic characteristics of Japanese patients with occult macular dystrophy (OMD) in a nationwide multicenter study.


METHODS
Twenty-three patients from 21 families with clinically diagnosed OMD were studied at 10 institutions throughout Japan. Ophthalmologic examinations including spectral-domain optic coherence tomography were performed. Patients were classified into two phenotype groups: a classical group having both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors, and a nonclassical group lacking at least one of these two features. Whole-exome sequencing, direct sequencing, and in silico molecular analysis were performed to detect the pathogenic RP1L1 variants. Statistical associations between the phenotype and genotypes based on the presence of pathogenic RP1L1 variants were investigated.


RESULTS
There were 12 families with the classical findings and 9 families with the nonclassical findings. Nine pathogenic RP1L1 missense variants were identified in 12 families (57%) including three reported variants, namely, p.R45W, p.S1199C, and p.G1200A, and six novel variants, p.G221R, p.T1194M, p.T1196I, p.G1200D, p.G1200V, and p.V1201G. The pathogenic missense variants in seven families (33%) were located between amino acid numbers 1196 and 1201. A significant association was found between the photoreceptor microstructural phenotypes and molecular genotypes.


CONCLUSIONS
The spectrum of the morphologic phenotypes and pathogenic RP1L1 variants was documented in a well-characterized Japanese cohort with OMD. A unique motif including six amino acids (1196-1201) downstream of the doublecortin domain could be a hot spot for RP1L1 pathogenic variants. The significant association of the morphologic phenotypes and genotypes indicates that there are two types of pathophysiology underlying the occult macular dysfunction syndrome: a hereditary OMD with the classical phenotype (Miyake's disease), and a nonhereditary OMD-like syndrome with progressive occult maculopathy.
Laboratory of Visual Physiology Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Meguro-ku, Tokyo, Japan 2Department of Ophthalmology, Keio University School of Medicine, Shinjyuku-ku, Tokyo, Japan 3UCL Institute of Ophthalmology, London, United Kingdom.
Kaoru
K
Fujinami
Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan.
Shuhei
S
Kameya
Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan.
Sachiko
S
Kikuchi
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan.
Shinji
S
Ueno
Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
Mineo
M
Kondo
Department of Ophthalmology, The Jikei University School of Medicine, Nishi-Shimbashi, Minato-ku,Tokyo, Japan.
Takaaki
T
Hayashi
Department of Ophthalmology, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.
Kei
K
Shinoda
Department of Ophthalmology, Iwate Medical University School of Medicine, Morioka, Iwate, Japan 10Department of Ophthalmology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Saitama, Japan.
Shigeki
S
Machida
Department of Ophthalmology, Kinki University Faculty of Medicine, Osaka-Sayama City, Osaka, Japan.
Kazuki
K
Kuniyoshi
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Meguro-ku, Tokyo, Japan.
Yuichi
Y
Kawamura
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Meguro-ku, Tokyo, Japan.
Masakazu
M
Akahori
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Meguro-ku, Tokyo, Japan.
Kazutoshi
K
Yoshitake
Department of Ophthalmology, The Jikei University School of Medicine, Nishi-Shimbashi, Minato-ku,Tokyo, Japan.
Satoshi
S
Katagiri
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan.
Ayami
A
Nakanishi
Department of Ophthalmology, Kinki University Faculty of Medicine, Osaka-Sayama City, Osaka, Japan.
Hiroyuki
H
Sakuramoto
UCL Institute of Ophthalmology, London, United Kingdom.
Yoko
Y
Ozawa
UCL Institute of Ophthalmology, London, United Kingdom.
Kazuo
K
Tsubota
Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan.
Kunihiko
K
Yamaki
Department of Ophthalmology, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.
Atsushi
A
Mizota
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan.
Hiroko
H
Terasaki
Aichi Medical University, Nagakute, Aichi, Japan.
Yozo
Y
Miyake
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Meguro-ku, Tokyo, Japan.
Takeshi
T
Iwata
Laboratory of Visual Physiology Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Meguro-ku, Tokyo, Japan.
Kazushige
K
Tsunoda
D000293:Adolescent; D000328:Adult; D000368:Aged; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D005838:Genotype; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008268:Macular Degeneration / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult
D005136:Eye Proteins; C474032:RP1L1 protein, human; D004247:DNA