SMN Gene dosage scans analysis suggests the gene conversion as a leading genetic alteration in families with no SMN1 deletion

Abstract

Introduction:Spinal muscular atrophy (SMA), an autosomal recessive neurogenetic disorder, is a leading genetic killer in young children and one of the common causes of disability presenting with proximal weakness in adults. The main pathogenic mutation is a deletion in the telomeric copy of the survival motor neuron gene (SMN1). Most carriers of SMA have one chromosome 5 with a normal SMN1 gene and one with a deleted SMN] gene. The gene dosage scan analysis has been optimized as a new method to determine the SMN1 and SMN2 copies number in l0 families with S_MA family history a.nd'at least one member with clinical features suggestive of SMA diagnosis. Material and Metl1ods:Total number of 36 subjects including 10 patients didn’t show SMN1-Exon7 deletion and their difierent descend families. Gene dosages scan analysis using multiplex PCR fragments analysis in 310 ABI genetic analyzer. Results:All patients included in this group showed no deletion for SMN1-Exon7 in restriction digest assays, 30% of them were females and 70% were males. 90% o1 patients showed two SMN1 copies combined with reduced number of SMN2 copies (i.e., 30% with no SMN2 copies, 60% with single copy of SMN2). Arounc‘ 10% of the same group showed single'SMNl and single SMN2 copy. The reduced number of SMN2 that correlates with SMA clinical feature associated with twc copies of SMN1 makes the gene conversion the most likely underlying mechanisn for 5ql3 region instability during the genetic information transmission betweex generations. This postulation also has been supported by the study findings ll parents SMN genetic profile as direct influence during the transmission of tlu inherited genetic material. Although this study also suggests a major paterna influence in SMN2 copies number, statistically the maternal influence i1 transmitting altered or reduced SMN2 copies number is more stronger than thr patemal influence in getting reduced SMN2 copies not balanced with SMN copies number (80% of mothers showed reduced or absent SMN2 copies compare with 66.67% of the fathers showed single copy ‘of SMN2 showed 0 to l SMN1 copies). Conclusion:These findings strongly suggestive of centromeric SMN1 gene conversion to an altered and or inactive telomeric SMN1 in SMA patient within the families included for this study.