Tomoto Yamamoto1, Hideyuki Sato2, Poh San Lai3, Dian Kesumapramudya Nurputra2, Nur Imma Fatimah Harahap2, Satoru Morikawa1, Noriyuki Nishimura1, Takashi Kurashige4, Tomohiko Ohshita4, Hideki Nakajima5, Hiroyuki Yamada6, Yoshinobu Nishida6, Soichiro Toda7, Jun-Ichi Takanashi7, Atsuko Takeuchi8, Yumi Tohyama9, Yuji Kubo10, Kayoko Saito10, Yasuhiro Takeshima11, Masafumi Matsuo12, Hisahide Nishio13. 1. Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan. 2. Department of Community Medicine and Social Health Care, 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. 7. Department of Pediatrics, Kameda Medical Center, Kamogawa, Chiba, Japan. 8. Kobe Pharmaceutical University, Kobe, Japan. 9. Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan. 10. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan. 11. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan. 12. Department of Medical Rehabilitation, Kobe Gakuin University, Kobe, Japan. 13. Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan. Electronic address: nishio@med.kobe-u.ac.jp.
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.
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.
Authors: Rodrigo de Holanda Mendonça; Ciro Matsui; Graziela Jorge Polido; André Macedo Serafim Silva; Leslie Kulikowski; Alexandre Torchio Dias; Evelin Aline Zanardo; Davi Jorge Fontoura Solla; Juliana Gurgel-Giannetti; Ana Carolina Monteiro Lessa de Moura; Gabriela Palhares Campolina Sampaio; Acary Souza Bulle Oliveira; Paulo Victor Sgobbi de Souza; Wladimir Bocca Vieira de Rezende Pinto; Eduardo Augusto Gonçalves; Igor Braga Farias; Flávia Nardes; Alexandra Prufer de Queiroz Campos Araújo; Wilson Marques; Pedro José Tomaselli; Mara Dell Ospedale Ribeiro; João Paulo Kitajima; Fabíola Paoli Monteiro; Jonas Alex Morales Saute; Michele Michelin Becker; Maria Luiza Saraiva-Pereira; Ana Carolina Brusius-Facchin; Vanessa van der Linden; Rodrigo Neves Florêncio; André Vinícius Soares Barbosa; Marcela Camara Machado-Costa; André Luiz Santos Pessoa; Leticia Silva Souza; Marcondes Cavalcante Franca; Fernando Kok; Umbertina Conti Reed; Edmar Zanoteli Journal: Neurol Genet Date: 2020-09-01
Authors: Kavita Praveen; Ying Wen; Kelsey M Gray; John J Noto; Akash R Patlolla; Gregory D Van Duyne; A Gregory Matera Journal: PLoS Genet Date: 2014-08-21 Impact factor: 5.917
Authors: Marianna A Maretina; Galina Y Zheleznyakova; Kristina M Lanko; Anna A Egorova; Vladislav S Baranov; Anton V Kiselev Journal: Curr Genomics Date: 2018-08 Impact factor: 2.236