MOLECULAR ANALYSIS OF CANDIDATE GENES ON CHROMOSOME 5Q13 IN AUTOSOMALRECESSIVE SPINAL MUSCULAR-ATROPHY - EVIDENCE OF HOMOZYGOUS DELETIONS OF THE SMN GENE IN UNAFFECTED INDIVIDUALS

Proximal spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of anterior horn cells in the spinal cord leading to weakness and wasting of voluntary muscles. Here we present the molecular analysis of both SMA candidate genes, the survival motor neuron gene (SMN; exons 7 and 8) and the ne uronal apoptosis inhibitory protein gene (NAIP; exons 5, 6 and 13), in 195 patients and 348 parents of SMA families mainly of German origin. The SMN gene is homozygously deleted for both exons 7 and 8 or exon 7 only in 96% of type I SMA, 94% of type II SMA and 82% of type III SMA as well as in 0.3% of SMA parents. The NAIP gene is homozygously dele ted in 46% of type I SMA, 17% of type II SMA, 7% of type III SMA and 2 % of SMA parents. The frequencies of deletions in patients for both ge nes, SMN and NAIP, correspond to those far the NAIP gene only. SMA pat ients of this series who did not show deletions were clinically indist inguishable from deleted patients. In addition to one unaffected mothe r of a type II SMA patient, we found homozygous deletions of the SMN g ene exons 7 and 8 in six further unaffected individuals, all sibs of t ype II and III patients. These belonged to four families with affected and unaffected sibs who showed identical haplotypes for all SMA flank ing markers; therefore, we had regarded these families as chromosome 5 unlinked. All seven unaffected individuals in whom we detected SMA de letions do not show any signs of muscle weakness and are physically in conspicuous. The largest divergence between age at onset of an affecte d subject and the present age of unaffected deleted sibs is four decad es now. The occurrence of SMN deletions in unaffected individuals sugg ests that other genes or mechanisms may be necessary to produce the SM A phenotype.