Telomeric Region of the Spinal Muscular Atrophy Locus Is Susceptible to Structural Variations.
Most patients with spinal muscular atrophy lack the survival motor neuron 1 gene (SMN1) in the telomeric region of the spinal muscular atrophy locus on chromosome 5q13. On the other hand, the copy number of SMN2, a centromeric homolog of SMN1, is increased in many of these patients. This study aimed to clarify the mechanism underlying these structural variations.



We determined the copy numbers of telomeric and centromeric genes in the spinal muscular atrophy locus of 86 patients and 22 control subjects using multiplex ligation-dependent probe amplification analysis. Then, we chose 74 patients lacking SMN1 exons 7 and 8, and compared their dataset with that of 22 control subjects retaining SMN1 exons 7 and 8.



The SMN2 copy number was shown to vary widely and to correlate with the disease severity of the patients. Interestingly, telomeric NAIP and telomeric GTF2H2 showed similar tendencies. We also noted positive correlations among the copy number of SMN2 and the telomeric genes of the spinal muscular atrophy locus. However, the copy numbers of centromeric NAIP and centromeric GTF2H2 were stable among the patients, with both approximating a value of two.



Our findings suggested that the telomeric region of the spinal muscular atrophy locus appears to be susceptible to structural variation, whereas the centromeric region is stable. Moreover, according to our results, new SMN2 copies may be generated in the telomeric region of the spinal muscular atrophy locus, supporting the SMN1-to-SMN2 gene conversion theory.
Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan.
Yoriko
Y
Noguchi
Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
Akira
A
Onishi
Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan.
Yuji
Y
Nakamachi
Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan.
Nobuhide
N
Hayashi
Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan.
Nur Imma Fatimah
NI
Harahap
Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan.
Mawaddah Ar
MA
Rochmah
Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan.
Ai
A
Shima
Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan.
Shinichiro
S
Yanagisawa
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.
Naoya
N
Morisada
Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
Taku
T
Nakagawa
Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
Kazumoto
K
Iijima
Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan.
Shimpei
S
Kasagi
Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan; Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
Jun
J
Saegusa
Department of Medical Education, Kobe University Graduate School of Medicine, Kobe, Japan.
Seiji
S
Kawano
Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan; The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe, Japan.
Masakazu
M
Shinohara
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan.
Shinya
S
Tairaku
Division of Child Neurology, Department of Neurology, National Hospital Organization Toneyama National Hospital, Toyonaka, Japan.
Toshio
T
Saito
Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
Yuji
Y
Kubo
Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
Kayoko
K
Saito
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.
Hisahide
H
Nishio
D000293:Adolescent; D000328:Adult; D000368:Aged; D002503:Centromere / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005091:Exons; D005260:Female; D056426:Genetic Loci; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics; D012720:Severity of Illness Index; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D055815:Young Adult
C496800:NAIP protein, human; D051616:Neuronal Apoptosis-Inhibitory Protein; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
MLPA analysis; SMA locus; centromeric; spinal muscular atrophy; structural variation; telomeric