title: 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.
authors: Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia.
authors: Miloš
authors: M
authors: Brkušanin
authors: Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia.
authors: Ana
authors: A
authors: Kosać
authors: Department of Genetic Research, Institute for Biological Research 'Siniša Stanković', University of Belgrade, Belgrade, Serbia.
authors: Vladimir
authors: V
authors: Jovanović
authors: Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia.
authors: Jovan
authors: J
authors: Pešović
authors: Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia.
authors: Goran
authors: G
authors: Brajušković
authors: Department of Neurology, University Children's Hospital, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.|Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
authors: Nikola
authors: N
authors: Dimitrijević
authors: Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia.|Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
authors: Slobodanka
authors: S
authors: Todorović
authors: Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia.
authors: Stanka
authors: S
authors: Romac
authors: Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia.|Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
authors: Vedrana
authors: V
authors: Milić Rašić
authors: Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia.
authors: Dušanka
authors: D
authors: Savić-Pavićević
mesh_terms: D017668:Age of Onset; D002648:Child; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D056915:DNA Copy Number Variations; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics; D010641:Phenotype; D055771:Serbia; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: C496800:NAIP protein, human; D009419:Nerve Tissue Proteins; D051616:Neuronal Apoptosis-Inhibitory Protein; C114841:SERF1A protein, human; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein