Intragenic variants in the
            <i>SMN1</i>
            gene determine the clinical phenotype in 5q spinal muscular atrophy

Mendonça, Rodrigo de Holanda; Matsui, Ciro; Polido, Graziela Jorge; Silva, André Macedo Serafim; Kulikowski, Leslie Domenici; Dias, Alexandre Torchio; Zanardo, Évelin Aline; Solla, Davi Jorge Fontoura; Gurgel-Giannetti, Juliana; Moura, Ana Carolina Monteiro Lessa de; Sampaio, Gabriela Palhares Campolina; Oliveira, Acary Souza Bullé; Souza, Paulo Victor Sgobbi de; Pinto, Wladimir Bocca Vieira de Rezende; Gonçalves, Eduardo Augusto; Farias, Igor Braga; Nardes, Flávia; Araújo, Alexandra Prüfer de Queiroz Campos; Marques, Wilson; Tomaselli, Pedro J.; Ribeiro, Mara Dell Ospedale; Kitajima, João Paulo; Monteiro, Fabíola Paoli; Saute, Jonas Alex Morales; Becker, Michele Michelin; Saraiva‐Pereira, Maria Luiza; Brusius-Facchin, Ana Carolina; Linden, Vanessa van der; Florêncio, Rodrigo; Barbosa, André Vinícius Soares; Machado‐Costa, Marcela Câmara; Pessoa, André Luiz Santos; Souza, Letícia Silva de; França, Marcondes Cavalcante; Kok, Fernando; Reed, Umbertina Conti; Zanoteli, Edmar

doi:10.1212/nxg.0000000000000505

Cited by 30 publications

(27 citation statements)

References 25 publications

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“…More surprisingly, 2 patients with a c.5C > T mutation (p.Ala2Val) in SMN1 showed phenotype type 3. There was a report of similar cases with a different mutation at the same location, c.5C > G (p.Ala2Gly) in SMN1, who presented with phenotype type 3 in spite of carrying only a single copy of SMN2 [27]. These findings, including ours, suggested that SMN1 with missense mutations, c.5C > T or c.5C > G, may produce SMN proteins with some function (hypomorphic mutation or leaky mutation).…”

Section: Relationship Between Clinical Phenotype and Smn2 Copy Numbersupporting

confidence: 63%

Phenotypes of SMA patients retaining SMN1 with intragenic mutation

Wijaya

Rohmah

Niba

et al. 2021

Brain and Development

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Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous deletion or intragenic mutation of the SMN1 gene. It is well-known that high copy number of its homologous gene, SMN2, modifies the phenotype of SMN1-deleted patients. However, in the patients with intragenic SMN1 mutation, the relationship between phenotype and SMN2 copy number remains unclear.Methods: We have analyzed a total of 515 Japanese patients with SMA-like symptoms (delayed developmental milestones, respiratory failures, muscle weakness etc.) from 1996 to 2019. SMN1 and SMN2 copy numbers were determined by quantitative polymerase chain reaction (PCR) method and/or multiplex ligation-dependent probe amplification (MLPA) method. Intragenic SMN1 mutations were identified through DNA and RNA analysis of the fresh blood samples.Results: A total of 241 patients were diagnosed as having SMA. The majority of SMA patients showed complete loss of SMN1 (n = 228, 95%), but some patients retained SMN1 and carried an intragenic mutation in the retaining SMN1 (n = 13, 5%). Ten different mutations were identified in these 13 patients, consisting of missense, nonsense, frameshift and splicing defect-causing mutations. The ten mutations were c.275G > C (p.Trp92Ser), c.819_820insT (p.Thr274Tyrfs*32), c.830A > G (p.Tyr277Cys), c.5C > T (p.Ala2Val), c.826 T > C (p.Tyr276His), c.79C > T (p.Gln27*), c.188C > A (p.Ser63*), c.422 T > C (p.Leu141Pro), c.835-2A > G (exon 7 skipping) and c.835-3C > A (exon 7 skipping). It should be noted here that some patients with milder phenotype carried only a single SMN2 copy (n = 3), while other patients with severe phenotype carried 3 SMN2 copies (n = 4).Conclusion: Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers.

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Section: Relationship Between Clinical Phenotype and Smn2 Copy Numbersupporting

confidence: 63%

Phenotypes of SMA patients retaining SMN1 with intragenic mutation

Wijaya

Rohmah

Niba

et al. 2021

Brain and Development

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“…Mendonca et al recently identified 16 patients with the exon 3 nonsense mutation c.460C>T (p.Gln154*). 16 All of the patients presented with a milder phenotype (SMA types 3 and 4), including 2 patients with 1 SMN2 copy and 10 patients with 2 SMN2 copies. The missense mutation p.Ala2Val has been found in several type 3 patients in the presence of 1 or 2 copies of SMN2 while type 1 patients with p.Trp92Ser were shown to have 3 SMN2 copies.…”

Section: Genotype Phenotype Associationmentioning

confidence: 97%

“…Recurrent variants have been found in exons 3 and 6, making these two exons hot spots for small mutations and missense mutations, respectively ( Figure 2D ). 15 , 16 Exon 6 codes for a domain in the protein which plays a role in protein oligomerization, and those patients with exon 6 missense mutations have decreased SMN protein self-oligomerization capacity. 15 The exon 6 p.Tyr272Cys missense mutation is the most frequently reported mutation in the SMN1 gene.…”

Section: Pathogenic Variantsmentioning

confidence: 99%

Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance

Keinath¹,

Prior²,

Prior³

2021

TACG

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Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder that causes degeneration of the alpha motor neurons from anterior horn cells in the spinal cord, which causes severe progressive hypotonia and muscular weakness. With a carrier frequency of 1 in 40-50 and an estimated incidence of 1 in 10,000 live births, SMA is the second most common autosomal recessive disorder. Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene SMN1 on 5q13 but keep the modifying SMN2 gene. The most common mutation causing SMA is a homozygous deletion of the SMN1 exon 7, which can be readily detected and used as a sensitive diagnostic test. Because SMN2 produces a reduced number of full-length transcripts, the number of SMN2 copies can modify the clinical phenotype and as such, becomes an essential predictive factor. Population-based SMA carrier screening identifies carrier couples that may pass on this genetic disorder to their offspring and allows the carriers to make informed reproductive choices or prepare for immediate treatment for an affected child. Three treatments have recently been approved by the Food and Drug Administration (FDA). Nusinersen increases the expression levels of the SMN protein using an antisense oligonucleotide to alter splicing of the SMN2 transcript. Onasemnogene abeparvovec is a gene therapy that utilizes an adenoassociated virus serotype 9 vector to increase low functional SMN protein levels. Risdiplam is a small molecule that alters SMN2 splicing in order to increase functional SMN protein. Newborn screening for SMA has been shown to be successful in allowing infants to be treated before the loss of motor neurons and has resulted in improved clinical outcomes. Several of the recommendations and guidelines in the review are based on studies performed in the United States.

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“…In addition, some missense variants in exon 1 of SMN1 are associated with a milder phenotype [44]. Two recurrent variants are c.5C>T (p.Ala2Val) and c.5C>G (p.Ala2Gly), which are considered hypomorphic alleles identified in SMA type III patients [51,52]. In fact, it has been shown in a SMA mouse model that the change p.Ala2Gly does not produce total loss of protein function [53] and no significant decrease of full-length SMN1 transcripts [43].…”

Section: The Known Validated Genotypesmentioning

confidence: 99%

The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

Costa-Roger

Blasco-Pérez

Cuscò

et al. 2021

IJMS

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After 26 years of discovery of the determinant survival motor neuron 1 and the modifier survival motor neuron 2 genes (SMN1 and SMN2, respectively), three SMN-dependent specific therapies are already approved by FDA and EMA and, as a consequence, worldwide SMA patients are currently under clinical investigation and treatment. Bi-allelic pathogenic variants (mostly deletions) in SMN1 should be detected in SMA patients to confirm the disease. Determination of SMN2 copy number has been historically employed to correlate with the phenotype, predict disease evolution, stratify patients for clinical trials and to define those eligible for treatment. In view that discordant genotype-phenotype correlations are present in SMA, besides technical issues with detection of SMN2 copy number, we have hypothesized that copy number determination is only the tip of the iceberg and that more deepen studies of variants, sequencing and structures of the SMN2 genes are necessary for a better understanding of the disease as well as to investigate possible influences in treatment responses. Here, we highlight the importance of a comprehensive approach of SMN1 and SMN2 genetics with the perspective to apply for better prediction of SMA in positive neonatal screening cases and early diagnosis to start treatments.

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Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy

Cited by 30 publications

References 25 publications

Phenotypes of SMA patients retaining SMN1 with intragenic mutation

Phenotypes of SMA patients retaining SMN1 with intragenic mutation

Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance

The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

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