Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients |
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| Authors: | Tomoto Yamamoto Hideyuki Sato Poh San Lai Dian Kesumapramudya Nurputra Nur Imma Fatimah Harahap Satoru Morikawa Noriyuki Nishimura Takashi Kurashige Tomohiko Ohshita Hideki Nakajima Hiroyuki Yamada Yoshinobu Nishida Soichiro Toda Jun-ichi Takanashi Atsuko Takeuchi Yumi Tohyama Yuji Kubo Kayoko Saito Yasuhiro Takeshima Masafumi Matsuo Hisahide Nishio |
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| Affiliation: | 1. Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan;2. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan;3. Department of Paediatrics, Yong Loo Lin School of Medicine, NUHS, National University of Singapore, Singapore;4. Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan;5. Department of Clinical Neuroscience and Neurology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan;6. Department of Pediatrics, Hyogo Prefectural Tsukaguchi Hospital, Amagasaki, Hyogo, Japan;g Department of Pediatrics, Kameda Medical Center, Kamogawa, Chiba, Japan;h Kobe Pharmaceutical University, Kobe, Japan;i Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan;j Institute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, Japan;k Department of Medical Rehabilitation, Kobe Gakuin University, Kobe, Japan |
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| Abstract: | Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by deletion or intragenic mutation of SMN1. SMA is classified into several subtypes based on clinical severity. It has been reported that the copy number of SMN2, a highly homologous gene to SMN1, is associated with clinical severity among SMA patients with homozygous deletion of SMN1. The purpose of this study was to clarify the genotype-phenotype relationship among the patients without homozygous deletion of SMN1. Methods: We performed molecular genetic analyses of SMN1 and SMN2 in 112 Japanese patients diagnosed as having SMA based on the clinical findings. For the patients retaining SMN1, the PCR or RT-PCR products of SMN1 were sequenced to identify the mutation. Results: Out of the 112 patients, 106 patients were homozygous for deletion of SMN1, and six patients were compound heterozygous for deletion of one SMN1 allele and intragenic mutation in the retained SMN1 allele. Four intragenic mutations were identified in the six patients: p.Ala2Val, p.Trp92Ser, p.Thr274TyrfsX32 and p.Tyr277Cys. To the best of our knowledge, all mutations except p.Trp92Ser were novel mutations which had never been previously reported. According to our observation, clinical severity of the six patients was determined by the type and location of the mutation rather than SMN2 copy number. Conclusion: SMN2 copy number is not always associated with clinical severity of SMA patients, especially SMA patients retaining one SMN1 allele. |
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| Keywords: | Spinal muscular atrophy SMN1 SMN2 Copy number Intragenic mutation |
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