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 disease.

Jędrzejowska, Maria; Milewski, Michał; Zimowski, Janusz; Borkowska, Julita; Kostera‐Pruszczyk, Anna; Sielska, Danuta; Jurek, Marta; Hausmanowa-Pétrusewicz, I

doi:10.18388/abp.2009_2521

Cited by 43 publications

(36 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our studied population, all patients with three SMN2 copies presented with milder types II and III phenotypes whereas all severe Type I carried two copies. Our data are in concordance with the reported inverse relationship between SMN2 copy number and disease severity [9,17,[27][28][29]. However, our results showed that phenotype cannot be predicted by the SMN2 copy number.…”

Section: Discussionsupporting

confidence: 92%

Genetic findings of Cypriot spinal muscular atrophy patients

et al. 2015

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disorder characterised commonly by proximal muscle weakness and wasting in the absence of sensory signs. Deletion or disruption of the SMN1 gene causes the disease. The SMN1 gene is located within an inverted duplication on chromosome 5q13 with the genes SMN2, NAIP and GTF2H2. MLPA analysis of 13 Cypriot SMA patients revealed that, 12 patients carried a homozygous SMN1 gene deletion and one patient carried two copies of the SMN1 gene. Two of 13 cases were a consequence of a paternally originating de novo mutation. Five genotypes were identified within the population, with the most frequent being a homozygous SMN1 and NAIP genes deletion. In conclusion, genotype-phenotype correlation revealed that SMN2 is inversely related to disease severity and that NAIP and GTF2H2 act as negative modifiers. This study provided, for the first time, a comprehensive overview of gene copy numbers and inheritance patterns within Cypriot SMA families.

show abstract

Section: Discussionsupporting

confidence: 92%

Genetic findings of Cypriot spinal muscular atrophy patients

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Several large studies have suggested that sex may have an influence on SMA phenotype [35,38]. Although the occurrence of SMA subtype was not stratified by sex in the Cure SMA sibling cohort, concordance and discordance rates in same-and different-sex sibships were not statistically significantly different.…”

Section: Discussionmentioning

confidence: 69%

“…A number of possible sources for variability in observed SMA phenotypes and general subtype concordance have been identified, including SMN2 copy number, aspects of motor function, sex, and birth order [34][35][36][37]. The severity of SMA is thought to be influenced by the amount of full-length SMN protein that is residually expressed.…”

Section: Discussionmentioning

confidence: 99%

Spinal Muscular Atrophy (SMA) Subtype Concordance in Siblings: Findings From the Cure SMA Cohort

Jones

Cook

Jarecki

et al. 2020

JND

View full text Add to dashboard Cite

Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous survival of motor neuron 1 (SMN1) gene disruption. Despite a genetic etiology, little is known about subtype concordance among siblings. Objective: To investigate subtype concordance among siblings with SMA. Methods: Cure SMA maintains a database of newly diagnosed patients with SMA, which was utilized for this research. Results: Among 303 sibships identified between 1996 and 2016, 84.8% were subtype concordant. Of concordant sibships, subtype distribution was as follows: Type I, 54.5%; Type II, 31.9%; Type III, 13.2%; Type IV, 0.4%. Subtype and concordance/discordance association was significant (Fisher's exact test; p < 0.0001). Among discordant sibships (chi-square test, p < 0.0001), Types II/III (52.2%) and Types I/II (28.3%) were the most common pairs. No association was found between sibling sex and concordance. Our findings show that most siblings with SMA shared the same subtype concordance (most commonly Type I). Conclusions: These data are valuable for understanding familial occurrence of SMA subtypes, enabling better individual treatment and management planning in view of new treatment options and newborn screening initiatives.

show abstract

“…Patients lacking SMN1 but carrying higher SMN2 copy numbers or SMN2 mutations that lead to greater SMN production exhibit a milder phenotype. [8][9][10][11][12][13][14][15] Various mouse models that recapitulate different SMA severities display complex pathology manifested by the loss of lower motor neurons, defects in neuromuscular junctions, and abnormalities in peripheral tissues, including the heart, muscles, intestines, liver, and spleen. [16][17][18][19][20][21][22][23][24][25] Suggesting a gender-specific role of SMN, heterozygous mice producing low levels of SMN show incidences of male infertility.…”

Section: Introductionmentioning

confidence: 99%

Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide

et al. 2017

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA), the leading genetic disease of children, is caused by low levels of survival motor neuron (SMN) protein. Here, we employ A15/283, an antisense oligonucleotide targeting a deep intronic sequence/structure, to examine the impact of restoration of SMN in a mild SMA mouse model. We show gender-specific amelioration of tail necrosis upon subcutaneous administrations of A15/283 into SMA mice at postnatal days 1 and 3. We also demonstrate that a modest increase in SMN due to early administrations of A15/283 dramatically improves testicular development and spermatogenesis. Our results reveal near total correction of expression of several genes in adult testis upon temporary increase in SMN during early postnatal development. This is the first demonstration of in vivo efficacy of an antisense oligonucleotide targeting a deep intronic sequence/structure. This is also the first report of gender-specific amelioration of SMA pathology upon a modest peripheral increase of SMN.

show abstract

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 disease.

Cited by 43 publications

References 30 publications

Genetic findings of Cypriot spinal muscular atrophy patients

Genetic findings of Cypriot spinal muscular atrophy patients

Spinal Muscular Atrophy (SMA) Subtype Concordance in Siblings: Findings From the Cure SMA Cohort

Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide

Contact Info

Product

Resources

About