SMNT and NAIP mutations in Canadian families with spinal muscular atrophy (SMA): Genotype/phenotype correlations with disease severity

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Abstract
Childhood-onset spinal muscular atrophy (SMA) is an autosomal recessive neuropathy characterized by selective degeneration of α-motor neuron cells of the spinal cord. Age of onset and motor development varies greatly among patients, but the molecular basis of this variability remains unclear. The SMA locus contains two copies of a 500-kb element and deletions within the telomeric element have been shown to be the most common cause of SMA. To study the relationship between genotype and phenotype, 60 SMA families, all but two of which are of French Canadian origin, were screened for deletions in the telomeric survival motor neuron (SMNT) and the intact neuronal apoptosis inhibitory protein (NAIP) genes. Combining these results with those obtained for the multicopy microsatellite marker Ag1-CA (D5S1556) indicated that there are at least two types of SMA alleles. Most type I SMA patients are homozygous for large scale deletions involving the entire SMNT gene as well as exons 5 and 6 of the NAIP gene. The strong association between the 100-bp allele of Ag1-CA and large scale deletions in populations of diverse ethnic origin suggests that this allele marks an unstable or founder SMA chromosome. In contrast, most chronic SMA patients have at least one SMA allele with either an intragenic SMNT deletion or a SMNC:SMNT chimeric gene which replaces the normal SMNT gene. The broad continuum of disease presentation in chronic SMA is most likely a consequence of the interaction between different SMA alleles. Am. J. Med. Genet. 72:51–58, 1997.