TY - JOUR
T1 - Novel RP1L1 variants and genotype-photoreceptor microstructural phenotype associations in cohort of Japanese patients with occult macular dystrophy
AU - Fujinami, Kaoru
AU - Kameya, Shuhei
AU - Kikuchi, Sachiko
AU - Ueno, Shinji
AU - Kondo, Mineo
AU - Hayashi, Takaaki
AU - Shinoda, Kei
AU - Machida, Shigeki
AU - Kuniyoshi, Kazuki
AU - Kawamura, Yuichi
AU - Akahori, Masakazu
AU - Yoshitake, Kazutoshi
AU - Katagiri, Satoshi
AU - Nakanishi, Ayami
AU - Sakuramoto, Hiroyuki
AU - Ozawa, Yoko
AU - Tsubota, Kazuo
AU - Yamaki, Kunihiko
AU - Mizota, Atsushi
AU - Terasaki, Hiroko
AU - Miyake, Yozo
AU - Iwata, Takeshi
AU - Tsunoda, Kazushige
N1 - Publisher Copyright:
© 2016, Association for Research in Vision and Ophthalmology Inc. All rights reserved.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - Electroretinogram
KW - Macular dystrophy
KW - Miyake’s disease
KW - Occular macular dystropphy
KW - RP1L1
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U2 - 10.1167/iovs.16-19670
DO - 10.1167/iovs.16-19670
M3 - Article
C2 - 27623337
AN - SCOPUS:84987923099
SN - 0146-0404
VL - 57
SP - 4837
EP - 4846
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 11
ER -