Tomoko Horinouchi1, Kandai Nozu2, Tomohiko Yamamura1, Shogo Minamikawa1, Takashi Omori3, Keita Nakanishi1, Junya Fujimura1, Akira Ashida4, Mineaki Kitamura5, Mitsuhiro Kawano6, Wataru Shimabukuro7, Chizuko Kitabayashi8, Aya Imafuku9, Keiichi Tamagaki10, Koichi Kamei11, Kenjirou Okamoto12, Shuichiro Fujinaga13, Masafumi Oka14, Toru Igarashi15, Akinori Miyazono16, Emi Sawanobori17, Rika Fujimaru18, Koichi Nakanishi19, Yuko Shima20, Masafumi Matsuo21, Ming Juan Ye1, Yoshimi Nozu1, Naoya Morisada1, Hiroshi Kaito1, Kazumoto Iijima1. 1. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan. 2. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan; nozu@med.kobe-u.ac.jp. 3. Clinical and Translational Research Center, Kobe University Hospital, Kobe, Japan. 4. Department of Pediatrics, Osaka Medical College, Osaka, Japan. 5. Department of Nephrology, Nagasaki University Hospital, Nagasaki, Japan. 6. Department of Rheumatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. 7. Department of Pediatrics, Japan Community Health Care Organization Kyushu Hospital, Sapporo, Hokkaido, Japan. 8. Department of Nephrology and Hypertension, Osaka City General Hospital, Osaka, Japan. 9. Department of Nephrology, Toranomon Hospital, Tokyo, Japan. 10. Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. 11. Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan. 12. Department of Urology, Ehime Prefectural Central Hospital, Ehime, Japan. 13. Division of Nephrology, Saitama Children's Medical Center, Saitama, Japan. 14. Department of Pediatrics, Faculty of Medicine Saga University, Saga, Japan. 15. Department of Pediatrics, Nippon Medical School, Tokyo, Japan. 16. Department of Pediatrics, Faculty of Medicine Kagoshima University, Kagoshima, Japan. 17. Department of Pediatrics, University of Yamanashi, Yamanashi, Japan. 18. Department of Pediatrics, Osaka General Hospital, Osaka, Japan. 19. Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan. 20. Department of Pediatrics, Wakayama Medical University, Wakayama, Japan; and. 21. Department of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University, Kobe, Japan.
Abstract
BACKGROUND: X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS. METHODS: We examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level. RESULTS: We detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001). CONCLUSIONS: We report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.
BACKGROUND:X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS. METHODS: We examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level. RESULTS: We detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001). CONCLUSIONS: We report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.
Authors: Mir Reza Bekheirnia; Berenice Reed; Martin C Gregory; Kim McFann; Alireza Abdollah Shamshirsaz; Amirali Masoumi; Robert W Schrier Journal: J Am Soc Nephrol Date: 2010-04-08 Impact factor: 10.121
Authors: Samar M Said; Mary E Fidler; Anthony M Valeri; Brooke McCann; Wade Fiedler; Lynn D Cornell; Mariam Priya Alexander; Ahmed M Alkhunaizi; Anne Sullivan; Carl H Cramer; Marie C Hogan; Samih H Nasr Journal: Kidney Int Rep Date: 2016-09-29