Phenotypes of SMA patients retaining SMN1 with intragenic mutation |
| |
| Authors: | Yogik Onky Silvana Wijaya Mawaddah Ar Rohmah Emma Tabe Eko Niba Naoya Morisada Yoriko Noguchi Yasufumi Hidaka Shiro Ozasa Takeshi Inoue Tomoyuki Shimazu Yuya Takahashi Takenori Tozawa Tomohiro Chiyonobu Takushi Inoue Tomoyoshi Shiroshita Atsushi Yokoyama Kentaro Okamoto Hiroyuki Awano Yasuhiro Takeshima Masakazu Shinohara |
| |
| Institution: | 1. Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan;2. Department of Neurology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia;3. Department of Clinical Genetics, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan;4. Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan;5. Department of Pediatrics, Kitakyushu Municipal Medical Center, Kitakyushu, Japan;6. Department of Pediatrics, Kumamoto University, Kumamoto, Japan;7. Department of Neonatology, Kumamoto City Hospital, Kumamoto, Japan;8. Department of Pediatrics, National Hospital Organization Kumamoto Saishunso Hospital, Kumamoto, Japan;9. Department of Pediatrics, Nagaoka Red Cross Hospital, Nagaoka, Japan;10. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan;11. Department of Pediatrics, National Hospital Organization Okayama Medical Center, Okayama, Japan;12. Faculty of Medical Rehabilitation, Kobe Gakuin University, Kobe, Japan;13. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan;14. Department of Pediatrics, Ehime Prefectural Imabari Hospital, Imabari, Japan;15. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan;p. Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Japan;q. Division of Child Neurology, Department of Neurology, National Hospital Organization Osaka Toneyama Medical Center, Toyonaka, Japan;r. Institute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, Japan |
| |
| Abstract: | BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous deletion or intragenic mutation of the SMN1 gene. It is well-known that high copy number of its homologous gene, SMN2, modifies the phenotype of SMN1-deleted patients. However, in the patients with intragenic SMN1 mutation, the relationship between phenotype and SMN2 copy number remains unclear.MethodsWe have analyzed a total of 515 Japanese patients with SMA-like symptoms (delayed developmental milestones, respiratory failures, muscle weakness etc.) from 1996 to 2019. SMN1 and SMN2 copy numbers were determined by quantitative polymerase chain reaction (PCR) method and/or multiplex ligation-dependent probe amplification (MLPA) method. Intragenic SMN1 mutations were identified through DNA and RNA analysis of the fresh blood samples.ResultsA total of 241 patients were diagnosed as having SMA. The majority of SMA patients showed complete loss of SMN1 (n = 228, 95%), but some patients retained SMN1 and carried an intragenic mutation in the retaining SMN1 (n = 13, 5%). Ten different mutations were identified in these 13 patients, consisting of missense, nonsense, frameshift and splicing defect-causing mutations. The ten mutations were c.275G > C (p.Trp92Ser), c.819_820insT (p.Thr274Tyrfs*32), c.830A > G (p.Tyr277Cys), c.5C > T (p.Ala2Val), c.826 T > C (p.Tyr276His), c.79C > T (p.Gln27*), c.188C > A (p.Ser63*), c.422 T > C (p.Leu141Pro), c.835-2A > G (exon 7 skipping) and c.835-3C > A (exon 7 skipping). It should be noted here that some patients with milder phenotype carried only a single SMN2 copy (n = 3), while other patients with severe phenotype carried 3 SMN2 copies (n = 4).ConclusionIntragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers. |
| |
| Keywords: | Spinal muscular atrophy Intragenic mutation RT-PCR Long-range PCR |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
