Fujinami Kaoru, Kameya Shuhei, Kikuchi Sachiko, Ueno Shinji, Kondo Mineo, Hayashi Takaaki, Shinoda Kei, Machida Shigeki, Kuniyoshi Kazuki, Kawamura Yuichi, Akahori Masakazu, Yoshitake Kazutoshi, Katagiri Satoshi, Nakanishi Ayami, Sakuramoto Hiroyuki, Ozawa Yoko, Tsubota Kazuo, Yamaki Kunihiko, Mizota Atsushi, Terasaki Hiroko, Miyake Yozo, Iwata Takeshi, Tsunoda Kazushige
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.
Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan.
Invest Ophthalmol Vis Sci. 2016 Sep 1;57(11):4837-46. doi: 10.1167/iovs.16-19670.
To determine the clinical and genetic characteristics of Japanese patients with occult macular dystrophy (OMD) in a nationwide multicenter study.
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.
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.
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.
在一项全国性多中心研究中确定日本隐匿性黄斑营养不良（OMD）患者的临床和遗传特征。
来自21个临床诊断为OMD家庭的23名患者在日本各地的10家机构接受研究。进行了包括光谱域光学相干断层扫描在内的眼科检查。患者被分为两个表型组：经典组，同时具有模糊的椭圆体带和光感受器指状交叉带缺失；非经典组，至少缺少这两个特征中的一个。进行全外显子组测序、直接测序和计算机分子分析以检测致病性RP1L1变异。研究基于致病性RP1L1变异的存在，表型与基因型之间的统计学关联。
有12个家庭有经典表现，9个家庭有非经典表现。在12个家庭（57%）中鉴定出9个致病性RP1L1错义变异，包括3个已报道的变异，即p.R45W、p.S1199C和p.G1200A，以及6个新变异，p.G221R、p.T1194M、p.T1196I、p.G1200D、p.G1200V和p.V1201G。7个家庭（33%）中的致病性错义变异位于氨基酸编号1196至1201之间。在光感受器微观结构表型和分子基因型之间发现了显著关联。
在一个特征明确的日本OMD队列中记录了形态学表型和致病性RP1L1变异的谱。在双皮质素结构域下游包括六个氨基酸（1196 - 1201）的独特基序可能是RP1L1致病性变异的热点。形态学表型和基因型的显著关联表明，隐匿性黄斑功能障碍综合征有两种病理生理学类型：具有经典表型的遗传性OMD（三宅病），以及伴有进行性隐匿性黄斑病变的非遗传性OMD样综合征。
