Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy

Abstract

Previous reports have established that the telomeric copy of the survival motor neuron (SMNT) gene and the intact copy of the neuronal apoptosis inhibitory protein (NAIP) gene are preferentially deleted in patients with spinal muscular atrophy (SMA). Although deletions or mutations in the SMNT gene are most highly correlated with SMA, it is not clear to what extent NAIP or other genes influence the SMA phenotype, or whether a small fraction of SMA patients actually have functional copies of both SMNT and NAIP. To evaluate further the part of SMNT in the development of SMA, we analyzed 280 asymptomatic SMA family members for the presence or absence of SMNT exons 7 and 8. We report the following observations: (i) 4% of the sample harbored a polymorphic variant of SMNT exon 7 that looks like a homozygous deletion; (ii) approximately 1% of the parents are homozygously deleted for both exons 7 and 8; (iii) one asymptomatic parent lacking both copies of SMNT exons 7 and 8 displays a 'subclinical phenotype' characterized by mild neurogenic pathology; (iv) another asymptomatic parent lacking both SMNT exons showed no signs of motor neuron disorder by clinical and neurodiagnostic analyses. The demonstration of polymorphic variants of exon 7 that masquerade as homozygous nulls, and the identification of SMA parents who harbor two disease alleles, serve as a caution to those conducting prenatal tests with these markers.

An essential SMN interacting protein (SIP1) is not involved in the phenotypic variability of spinal muscular atrophy (SMA)

“…The intrafamilial variability is especially interesting since the milder affected sibs or the unaffected SMN1 deleted sibs are in most cases females. [5][6][7][8]11 The discovery of the modifying factor that prevents these individuals from developing SMA might be of therapeutic relevance.…”

“…4 Nevertheless, there are quite a few reports in which large phenotypic variability has been described among sibs with identical 5q13 homologs. [5][6][7][8] The main SMA determining gene is the survival motor neuron gene (SMN1) which in SMA patients is mutated in about 96%. [9][10][11] Of the 5q13-linked SMA patients, 96.4% show homozygous absence of SMN1 exons 7 and 8 or exon 7 only, whereas 3.6% present a compound heterozygosity with a subtle mutation on one chromosome and a deletion/gene conversion on the other chromosome.…”

Best practice guidelines for molecular analysis in spinal muscular atrophy

“…10,11,31 Parents of a SMA patient may actually have a homozygous SMN1 deletion themselves. Although it is hard to predict whether the parental SMN1 deletion allele that had not been transmitted to the affected child may have a pathogenic effect at all, it is our opinion that it cannot be considered simply as a non-risk SMN1 allele.…”

Correlation of SMNt and SMNc gene copy number with age of onset and survival in spinal muscular atrophy

“…[7][8][9][10][11] Additional work with the multicopy markers C212 and C272 showed an association of specific numbers of marker copies with the severity of the disease, and a model was proposed to account for the different phenotypes observed by a system of mild and severe alleles. 12 However, later studies [13][14][15] described homozygous deletions of the SMNt gene in a small number of unaffected individuals (siblings and parents of affected individuals), thus casting some doubt upon this gene as the only causal gene for SMA. The case for at least partial involvement of the NAIP gene in the SMA phenotype was supported by several studies which demonstrated that the severe SMA type I was associated with a higher frequency of homozygous deletions of NAIP than the milder forms [16][17][18] A study by Somerville et al 19 quoted a five-fold increased risk of type I SMA associated with absence of the NAIP gene.…”