Joint effect of the SMN2 and SERF1A genes on childhood-onset types of spinal muscular atrophy in Serbian patients

Abstract

Spinal muscular atrophy (SMA) is caused by functional loss of the survival of motor neuron 1 (SMN1) gene. Despite genetic homogeneity, phenotypic variability indicates the involvement of disease modifiers. SMN1 is located in 5q13.2 segmental duplication, enriched in genes and prone to unequal rearrangements, which results in copy number polymorphism (CNP). We examined the influence of CNP of 5q13.2 genes and their joint effect on childhood-onset SMA phenotype. Multiplex ligation-dependent probe amplification (MLPA) was used to construct 5q13.2 alleles and assess copy number of the SMN2, small EDRK-rich factor 1A (SERF1A) and NLR family apoptosis inhibitory protein (NAIP) genes in 99 Serbian patients with SMN1 homozygous absence (23-type I, 37-type II and 39-mild type III) and 122 patients' parents. Spearman rank test was performed to test correlation of individual genes and SMA type. Generalized linear models and backward selection were performed to obtain a model explaining phenotypic variation with the smallest set of variables. 5q13.2 alleles most commonly associated with type I harbored large-scale deletions, while those detected in types II and III originated from conversion of SMN1 to SMN2. Inverse correlation was observed between SMN2, SERF1A and NAIP CNP and SMA type (P=2.2e-16, P=4.264e-10, P=2.722e-8, respectively). The best minimal model describing phenotypic variability included SMN2 (P<2e-16), SERF1A (P<2e-16) and their interaction (P=0.02628). SMN2 and SERF1A have a joint modifying effect on childhood-onset SMA phenotype.

SMN1 copy number as a modifying factor of survival in Serbian patients with sporadic amyotrophic lateral sclerosis

“…Despite the absence of association in our study, a recent study by Kano et al [24] reported that the NAIP protein level in ALS patients was lower by nearly half compared to healthy controls. These latest findings and the implication of SERF1 CNVs in the SMA clinical outcome justify research efforts focused on the role of NAIP and SERF1 CNVs in SALS [15].…”

“…Since MLPA is a relative quantification technique, all samples were compared with 15 reference samples using the Coffalyser.Net software (MRC-Holland, Amsterdam, the Netherlands). Ratios of MLPA probes specific for 5q13.2 genes and the assigned copy numbers were as previously described [15]. Reproducibility of the MLPA method was determined by running ~30% of randomly selected samples in independent duplicates and by obtaining identical results between the replicas.…”

“…The NAIP protein acts as a neuroprotector by the inhibition of motor neuron apoptosis. Deletions of telomeric copies of NAIP and particularly SERF1 mostly accompany deletions of the neighboring SMN1 gene in SMA patients [15]. However, duplications of NAIP were detected in ~7.5% of chromosomes carrying one SMN1 copy [15].…”

Opening the window: The case for carrier and perinatal screening for spinal muscular atrophy

“…For example, patients with 4 copies of SMN2 can present with anywhere from type 1 to type 4 disease [27,39]. There are other genetic modifiers of SMA disease severity, such as SERF1A and PLS3 [40][41][42], which further confounds a prediction of disease severity based solely on SMN2 copy number (of note, the role of PLS3 as a modifier of SMA disease severity has not been supported in some mouse models of SMA [43]). Thus, clinical assessment of peak motor function still provides one of the best predictors of disease severity and life expectancy.…”

Genotipe-phenotipe correlation in spinal muscle atrophy (SMA)

“…34 Razvojem novih metoda za kvantitativno određivanje broja kopija gena pokazano je da između težine kliničke slike i broja genskih kopija SMN2 postoji inverzna korelacija, što pokazuju i rezultati naše studije. 19,23,35,36 Zaključak Ovim istraživanjem uspostavljena je značajna korelacija između broja kopija SMN2 gena i fenotipa SMA pacijenata. Zasigurno je da postoje i drugi faktori koji mogu da utiču na kliničku ekspresiju bolesti, te stoga, uzimajući u obzir njenu genetičku osnovu, sve veću zastupljenost asimptomatskih heterozigotnih nosilaca delecije SMN1 gena u populaciji, ali i činjenicu da još uvek ne postoji adekvatna kauzalna terapija, genetsko testiranje treba da bude ključni korak za dijagnozu ovog neuromišićnog obolenja i za adekvatno genetsko savetovanje.…”