Human Molecular Genetics, Vol 8, 2525-2532, Copyright © 1999 by Oxford University Press
T Vitali, V Sossi, F Tiziano, S Zappata, A Giuli, M Paravatou-Petsotas, G Neri and C Brahe
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular
disorder which presents with various clinical phenotypes ranging from
severe to very mild. All forms are caused by the homozygous absence of the
survival motor neuron ( SMN1 ) gene. SMN1 and a nearly identical copy (
SMN2 ) are located in a duplicated region at 5q13 and encode identical
proteins. The genetic basis for the clinical variability of SMA remains
unclear, but it has been suggested that the copy number of SMN2 could
influence the disease severity. We have assessed the number of SMN2 genes
in patients with different clinical phenotypes by fluorescence in situ
hybridization (FISH) using as SMN probe a mixture of small specific DNA
fragments. Gene copy number was established by FISH on interphase nuclei,
but the presence of two SMN2 genes on the same chromosome could also be
revealed by FISH on metaphase spreads. All patients had at least two SMN2
genes. We found two or three copies of SMN2 in severely affected type I
patients, three copies in intermediately affected type II patients,
generally four copies in mildly affected type III patients and four or
eight copies in patients with very mild adult-onset SMA. No alterations of
the genes were detected by Southern blot and sequence analysis, suggesting
that all gene copies of SMN2 were intact. These data provide additional
evidence that the SMN2 genes modulate the disease severity and suggest that
knowledge of the gene copy number could be of some prognostic value.
ARTICLES
Detection of the survival motor neuron (SMN) genes by FISH: further evidence for a role for SMN2 in the modulation of disease severity in SMA patients
Institute of Medical Genetics, Catholic University, Largo F. Vito 1, I- 00168 Rome, Italy
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