Telomeric Region of the Spinal Muscular Atrophy Locus Is Susceptible to Structural Variations |
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| Affiliation: | 1. Paediatric Neurology, Catholic University, Rome, Italy;2. Centro Clinico Nemo, Policlinico Gemelli, Rome, Italy;3. Institute of Genomic Medicine, Catholic University, Rome, Italy;4. UOC Neurologia, Fondazione Policlinico Gemelli, Rome, Italy;1. Nemours Biomolecular Core Laboratory, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA;2. Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA;3. Neurogenetics Research Program, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA;4. Department of Neurology, Johns Hopkins University, Baltimore, MD, USA;5. Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA;6. Center for Pediatric Research, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA;7. Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA;8. Department of Biological Sciences, University of Delaware, Newark, DE, USA;1. Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan;2. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan;3. Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan;4. Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;5. Department of Pediatrics and Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan;6. Genephile Bioscience Laboratory, Ko''s Obstetrics and Gynecology, Taipei, Taiwan |
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| Abstract: | BackgroundMost 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.MethodsWe 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.ResultsThe 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.ConclusionOur 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. |
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| Keywords: | spinal muscular atrophy SMA locus telomeric centromeric structural variation MLPA analysis |
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