title: Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients.
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.
  
  
  CONCLUSIONS
  SMN2 copy number is not always associated with clinical severity of SMA patients, especially SMA patients retaining one SMN1 allele.
authors.affiliation: 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.
authors.forename: Tomoto
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Paediatrics, Yong Loo Lin School of Medicine, NUHS, National University of Singapore, Singapore.
authors.forename: Poh San
authors.initials: PS
authors.lastname: Lai
authors.affiliation: Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Dian Kesumapramudya
authors.initials: DK
authors.lastname: Nurputra
authors.affiliation: Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Nur Imma Fatimah
authors.initials: NI
authors.lastname: Harahap
authors.affiliation: 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.
authors.forename: Satoru
authors.initials: S
authors.lastname: Morikawa
authors.affiliation: 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.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurashige
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohshita
authors.affiliation: Department of Clinical Neuroscience and Neurology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Pediatrics, Hyogo Prefectural Tsukaguchi Hospital, Amagasaki, Hyogo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Pediatrics, Hyogo Prefectural Tsukaguchi Hospital, Amagasaki, Hyogo, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Nishida
authors.affiliation: Department of Pediatrics, Kameda Medical Center, Kamogawa, Chiba, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Toda
authors.affiliation: Department of Pediatrics, Kameda Medical Center, Kamogawa, Chiba, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Takanashi
authors.affiliation: Kobe Pharmaceutical University, Kobe, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Tohyama
authors.affiliation: Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kubo
authors.affiliation: Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeshima
authors.affiliation: Department of Medical Rehabilitation, Kobe Gakuin University, Kobe, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: 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.
authors.forename: Hisahide
authors.initials: H
authors.lastname: Nishio
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000465:Algorithms; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000145:classification / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger; D012720:Severity of Illness Index; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
keywords: Copy number; Intragenic mutation; SMN1; SMN2; Spinal muscular atrophy