ABSTRACT
BACKGROUND: Spinal muscular atrophy (SMA) is the second most common disease with autosomal recessive mode of inheritance in children and characterized by degeneration of anterior horn cells of the spinal cord resulting in weakness and wasting of voluntary muscles. This disease is caused by deletion of many candidate genes including SMN, p44, NAIP on chromosome 5q11.2-13.3. Although molecular characteristics of candidate genes were identified, genotype-phenotype correlation has not been clearly elucidated yet. Nevertheless, gene conversion, previously described as simply as gene deletion, appears to be very important mechanism as a molecular pathogenesis, and even makes more difficult to pursue the correlation. PURPOSE: This study was aimed to define the correlation between genotype and phenotype of SMA in Korean patients. The significance of SMN gene as well as NAIP gene, p44 gene in the progress of disease process and phenotypic correlation with gene conversion was evaluated. This study was also undertaken to determine the frequency of gene rearrangements in normal population. METHOD: Eight type I SMA patients and two type II SMA patients were studied. SMN, NAIP, and p44 gene deletion were analyzed by PCR amplification and restriction enzyme digestion with DraI, DdeI and AluI, respectively. p44 gene was also analyzed by SSCP. Gene conversion was defined by centromeric and telomeric SMN gene exon 7 to exon 8 PCR amplification followed by DdeI restiction enzyme digestion. RESULT: 1) Five of eight type I patients showed deletion of SMN, NAIP and p44 gene, while the rest of type 1 and all type II patients showed deletion of SMN gene only. 2) We examined SMN and NAIP gene deletion on 100 normal newborns, which showed the deletion of centromeric SMN gene in two newborns, the relative frequency of 2% in gene rearrangement. 3) There was one case of type I SMA showing deletion of telomeric SMN exon 7 but not SMN exon 8 suggestive of gene conversion occurred during the recombination as a molecular pathogenesis. CONCLUSION: The major deletion of SMA candidate genes, SMN, NAIP, and p44 gene appear to be involved in severe phenotype since these three candidate genes deletion were noted only in type 1 cases. However, SMN gene deletion only identified both in type 1 and type 2 explains that SMN gene may plan an major role in the pathogenesis of SMA and also suggests that other factors may be affecting the severity in spinal muscular atrophy. One patient with type I which showed the conversion of the centromeric SMN gene to the teleomeric gene strongly supports that SMN gene copy number may not be correlated with the severity in SMA. Our molecular findings suggest that phenotype is not clearly correlated with genotype. Prenatal screening should be carefully undertaken to interpretate because of high frequency of gene rearrangements in normal populations.