Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the … (original) (raw)
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Acta biochimica Polonica, 2009
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. It is characterized by significant phenotype variability. In this study, we analyzed possible phenotype modifiers of the disease - the size of the deletion in the SMA region, the number of SMN2 gene copies, as well as the effect of gender. Among the factors analyzed, two seem to influence the SMA phenotype: the number of SMN2 gene copies and a deletion in the NAIP gene. A higher number of SMN2 copies makes the clinical symptoms more benign, and the NAIP gene deletion is associated with a more severe phenotype. The influence of gender remains unclear. In a group of 1039 patients, 55% of whom were male, the greatest disproportion was in the SMA1 (F/M = 0.78) and SMA3b (F/M = 0.45) forms. In SMA1 a deletion in the NAIP gene was seen twice as frequently in girls compared to boys. In three patients, we observed genotypes atypical for the chronic forms of SMA: two patients ...
Vojnosanitetski pregled, 2015
Background/Aim. Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of alpha motor neurons in the spinal cord and the medulla oblongata, causing progressive muscle weakness and atrophy. The aim of this study was to determine association between the SMN2 gene copy number and disease phenotype in Serbian patients with SMA with homozygous deletion of exon 7 of the SMN1 gene. Methods. The patients were identified using regional Serbian hospital databases. Investigated clinical characteristics of the disease were: patients? gender, age at disease onset, achieved and current developmental milestones, disease duration, current age, and the presence of the spinal deformities and joint contractures. The number of SMN1 and SMN2 gene copies was determined using real-time polymerase chain reaction (PCR). Results. Among 43 identified patients, 37 (86.0%) showed homozygous deletion of SMN1 exon 7. One (2.7%) of 37 patients had SMA type I with 3 SMN2 copie...
2022
SMA (spinal muscular atrophy) is an autosomal recessive neuromuscular disease that causes muscle atrophy and weakness. SMA is diagnosed by homozygous deletion in exon 7 of the SMN1 gene. However, mutations in other genes in the SMA region may contribute to the disease. These include SMN2, which is a pseudogene of SMN1, as well as NAIP and GTF2H2. Within the scope of our study, 58 SMA patients and 40 healthy controls were analyzed in 2018–2021. SMN1 and SMN2 copy numbers were retrospectively included in the study. NAIP gene analyzes were performed by multiplex PCR method and GTF2H2 analyzes were performed by RFLP method respectively. We detected a significant correlation between clinical subtypes (type 2 and type 3) and ambulation status (p = 0.003) and HFMSE scores (p = 0.0063) of 27 pediatric SMA patients compared with separately. Highly differences were determined between SMN2 copy numbers and the SMA subtypes (p = 0.00001). Also, the NAIP gene (p = 0,0095) and the GTF2H2 gene (p ...
Gene deletions in spinal muscular atrophy
Two candidate genes (NAIP and SMN) have recently been reported for childhood onset spinal muscular atrophy (SMA). Although affected subjects show deletions of these genes, these deletions can lead to either a very mild or a severe phenotype. We have analysed a large number of clinically well defined patients, carriers, and normal controls to assess the frequency and extent of deletions encompassing both of these genes. A genotype analysis indicates that more extensive deletions are seen in the severe form of SMA than in the milder forms. In addition, 1 center dot 9% of phenotypically normal carriers are deleted for the NAIP gene; no carriers were deleted for the SMN gene. Our data suggest that deletions in both of these genes, using the currently available assays, are associated with both a severe and very mild phenotype.
Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy
Neurology Genetics, 2020
ObjectiveThe aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number.MethodsFour hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing.ResultsFour hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous pati...
Molecular Analysis of Spinal Muscular Atrophy: a genotyping protocol based on TaqMan® real-time PCR
Genetics and Molecular Biology, 2012
The homozygous deletions of exons 7 and 8 of the SMN1 gene were found in 94% and 87% of the patients. Exon 5 of the NAIP gene was deleted in 70%, but its deletion was more frequent in SMA type I (93%) as compared to type II (54%) and type III (43%). Seven patients with SMA diagnosis did not show any of the above homozygous deletions. All 230 control subjects had at least one copy of both SMN1 and NAIP genes, as expected. Conclusion: Our results demonstrate that the deletion rate (94%) of the SMN1 gene in Saudi SMA patients is similar, irrespective of types, compared with patients of other ethnic groups. We also show that the incidence of NAIP deletion is higher in the more severe SMA cases and the dual deletion of the SMN1 and NAIP genes are more common in Saudi SMA type I patients compared with patients of other ethnic groups.
Molecular analysis of the SMN1 and NAIP genes in Iranian patients with spinal muscular atrophy
ANNALS-ACADEMY …, 2007
Introduction: Childhood-onset proximal spinal muscular atrophies (SMAs) are an autosomal recessive, clinically heterogeneous group of neuropathies characterised by the selective degeneration of anterior horn cells. SMA has an estimated incidence of 1 in 10,000 live births. The causative genes are survival motor neuron (SMN) gene and neuronal apoptosis inhibitory protein (NAIP) gene. Deletions of the telomeric copy of SMN gene (SMN1) have been reported in 88.5% to 95% of SMA cases, whereas the deletion rate for NAIP gene (NAIP) is between 20% and 50% depending on the disease severity. The main objective of this study was to genetically characterise the childhood onset of SMA in Iran. Materials and Methods: Molecular analysis was performed on a total of 75 patients with a clinical diagnosis of SMA. In addition to common PCR analysis for SMN1 exons 7 and 8, we analysed NAIP exons 4 and 5, along with exon 13, as a internal control, by bi-plex PCR. Results: The homozygous-deletion frequency rate for the telomeric copy of SMN exons 7 and 8 in all types of SMA was 97%. Moreover, exons 5 and 6 of NAIP gene were deleted in approximately 83% of all SMA types. Three deletion haplotypes were constructed by using SMN and NAIP genotypes. Haplotype A, in which both genes are deleted, was seen in approximately 83% of SMA types I and II but not type III. It was also found predominantly in phenotypically severe group with an early age of onset (i.e., less than 6-month-old). We also report 34 of our prenatal diagnosis. Conclusions: To our knowledge, the present study is the first one giving detailed information on SMN and NAIP deletion rates in Iranian SMA patients. Our results show that the frequency of SMN1 homozygous deletions in Iran is in agreement with previous studies in other countries. The molecular analysis of SMA-related gene deletion/s will be a useful tool for pre-and postnatal diagnostic.
SMN2 and NAIP gene dosages in Vietnamese patients with spinal muscular atrophy
Pediatrics International, 2008
Background: The SMN1 gene is now recognized as a spinal muscular atrophy (SMA)-causing gene, while SMN2 and NAIP have been characterized as a modifying factor of the clinical severity of SMA. Gene dosage of SMN2 is associated with clinical severity of SMA. But the relationship between gene dosage of NAIP and clinical severity of SMA remains to be clarified, although complete deletion of NAIP is frequent in type I patients.Methods: To evaluate the contribution of the SMN2 and NAIP gene dosages to SMA, quantitative real-time polymerase chain reaction was used to measure copy numbers of SMN2 and NAIP in 34 Vietnamese SMA patients lacking SMN1 (13 type I, 11 type II and 10 type III patients).Results: The SMN2 copy number in type I patients was significantly lower than that in type II–III patients, which was compatible with the previous reports. In contrast, 25 out of 34 patients had only zero or one copy of NAIP, while 50 out of 52 controls had two or more copies. For NAIP (+) genotype, six out of 13 type I patients, eight out of 11 type II patients and six out of 10 type III patients carried one NAIP copy.Conclusions: The SMN2 copy number was related to the clinical severity of SMA among Vietnamese patients. The presence of one NAIP copy, that is, heterozygous NAIP deletion, was common in Vietnamese SMA, regardless of clinical phenotype.
Genetika, 2001
Polymerase chain reaction with subsequent SSCP (single-strand DNA conformational polymorphism) and restriction (BselI restriction endonuclease) analyses were used to type the DNA samples of affected individuals and their relatives from 23 Russian families with high risk of spinal muscular atrophy (SMA) residing in the northwestern region of Russia. Deletions of exon 7 of the SMN gene were found in 96% of the individuals examined. The frequency of homozygous deletion of exons 7 and 8 of the SMN1 gene was 65%. The frequency of homozygous isolated deletion of the SMN1 gene exon 7 among the SMA patients was 4.3%. Homozygous deletion of exon 5 of the NAIP gene was found in 22% of SMA patients. In SMA patients, a total of seven deletion types involving the SMN1, NAIP, and SMN2 genes were detected. Deletion of exons 7 and 8 of the SMN1 gene was the most common mutation associated with SMA in patients from the northwestern Russia.