Kaoru Fujinami1, Shuhei Kameya2, Sachiko Kikuchi2, Shinji Ueno3, Mineo Kondo4, Takaaki Hayashi5, Kei Shinoda6, Shigeki Machida7, Kazuki Kuniyoshi8, Yuichi Kawamura9, Masakazu Akahori9, Kazutoshi Yoshitake9, Satoshi Katagiri5, Ayami Nakanishi3, Hiroyuki Sakuramoto8, Yoko Ozawa10, Kazuo Tsubota10, Kunihiko Yamaki2, Atsushi Mizota6, Hiroko Terasaki3, Yozo Miyake11, Takeshi Iwata9, Kazushige Tsunoda12. 1. 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. 2. Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan. 3. Department of Ophthalmology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan. 4. Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Mie, Japan. 5. Department of Ophthalmology, The Jikei University School of Medicine, Nishi-Shimbashi, Minato-ku,Tokyo, Japan. 6. Department of Ophthalmology, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan. 7. Department of Ophthalmology, Iwate Medical University School of Medicine, Morioka, Iwate, Japan 10Department of Ophthalmology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Saitama, Japan. 8. Department of Ophthalmology, Kinki University Faculty of Medicine, Osaka-Sayama City, Osaka, Japan. 9. Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Meguro-ku, Tokyo, Japan. 10. UCL Institute of Ophthalmology, London, United Kingdom. 11. Aichi Medical University, Nagakute, Aichi, Japan. 12. Laboratory of Visual Physiology Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Meguro-ku, Tokyo, Japan.
Abstract
PURPOSE: 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.
PURPOSE: 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.
Authors: Kamron N Khan; Melissa Kasilian; Omar A R Mahroo; Preena Tanna; Angelos Kalitzeos; Anthony G Robson; Kazushige Tsunoda; Takeshi Iwata; Anthony T Moore; Kaoru Fujinami; Michel Michaelides Journal: Ophthalmology Date: 2018-01-06 Impact factor: 12.079