Arima syndrome caused by CEP290 specific variant and accompanied with pathological cilium; clinical comparison with Joubert syndrome and its related diseases |
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Authors: | Masayuki Itoh Shuhei Ide Yuji Iwasaki Takashi Saito Keishi Narita Hongmei Dai Shinji Yamakura Takeki Furue Hirotsugu Kitayama Keiko Maeda Eihiko Takahashi Kiyoshi Matsui Yu-ichi Goto Sen Takeda Masataka Arima |
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Affiliation: | 1. Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Kodaira, Japan;2. Division of Pediatrics, Tokyo Metropolitan Tobu Medical Center for Persons with Developmental and Multiple Disabilities, Tokyo, Japan;3. Department of Anatomy and Cell Biology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan;4. Tsubasa Shizuoka, Shizuoka, Japan;5. Department of Pediatric Nephrology, Hiroshima Prefectural Hospital, Hiroshima, Japan;6. Department of Nephrology, Shizuoka Children’s Hospital, Shizuoka, Japan;g. Department of Pediatrics, Shizuoka Iryo-Fukushi Center, Shizuoka, Japan;h. Division of Nephrology, Kanagawa Children’s Medical Center, Yokohama, Japan;i. Division of General Medicine, Kanagawa Children’s Medical Center, Yokohama, Japan |
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Abstract: | ObjectiveArima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD.Patients and methodsWe performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients.ResultsAll patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290?kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm.ConclusionAS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome. |
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Keywords: | Arima syndrome Joubert syndrome Joubert syndrome related diseases Cilium |
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