A novel nonsense SMC1A mutation in a patient with intractable epilepsy and cardiac malformation

Chinen, Yoshiaki; Nakamura, Sadao; Kaneshi, Takuya; Nakayashiro, Mami; Yanagi, Kumiko; Kaname, Tadashi; Naritomi, Kenji; Nakanishi, Koichi

doi:10.1038/s41439-019-0053-y

Cited by 11 publications

(12 citation statements)

References 20 publications

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“…The authors highlighted that SMC1A truncating mutations were seen only in females who often lack the typical features of CdLS but presented with drug‐resistant cluster seizures and moderate–severe intellectual disability (Symonds et al, 2017). Since then, there have been two more case reports revealing that a missense variant of SMC1A could cause severe epilepsy without the characteristics of CdLS; and a novel SMC1A truncating mutation could result in the CdLS phenotype (Chinen et al, 2019; Oguni et al, 2019). The genotype–phenotype of SMC1A , therefore, may be more complex and require further accumulated data.…”

Section: Discussionmentioning

confidence: 99%

“…Missense mutations and small in-frame deletions in SMC1A were first identified in patients with Cornelia de Lange syndrome (CdLS), a very rare condition (Deardorff et al, 2007;Musio et al, 2006) et al, 2017). Since then, there have been two more case reports revealing that a missense variant of SMC1A could cause severe epilepsy without the characteristics of CdLS; and a novel SMC1A truncating mutation could result in the CdLS phenotype (Chinen et al, 2019;Oguni et al, 2019). The genotype-phenotype of SMC1A, therefore, may be more complex and require further accumulated data.…”

Section: Patientmentioning

confidence: 99%

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Genetic analysis using targeted exome sequencing of 53 Vietnamese children with developmental and epileptic encephalopathies

Hieu

Thu

Ngan

et al. 2022

American J of Med Genetics Pt A

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Developmental and epileptic encephalopathies (DEE) refers to a group of rare and severe neurodevelopmental disorders where genetic etiologies can play a major role. This study aimed to elucidate the genetic etiologies of a cohort of 53 Vietnamese patients with DEE. All patients were classified into known electroclinical syndromes where possible. Exome sequencing (ES) followed by a targeted analysis on 294 DEE‐related genes was then performed. Patients with identified causative variants were followed for 6 months to determine the impact of genetic testing on their treatment. The diagnostic yield was 38.0% (20/53), which was significantly higher in the earlier onset group (<12 months) than in the later onset group (≥12 months). The 19 identified variants belonged to 11 genes with various cellular functions. Genes encoding ion channels especially sodium voltage‐gated channel were the most frequently involved. Most variants were missense variants and located in key protein functional domains. Four variants were novel and four had been reported previously but in different phenotypes. Within 6 months of further follow‐up, treatment changes were applied for six patients based on the identified disease‐causing variants, with five patients showing a positive impact. This is the first study in Vietnam to analyze the genetics of DEE. This study confirms the strong involvement of genetic etiologies in DEE, especially early onset DEE. The study also contributes to clarify the genotype–phenotype correlations of DEE and highlights the efficacy of targeted ES in the diagnosis and treatment of DEE.

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Section: Discussionmentioning

confidence: 99%

Section: Patientmentioning

confidence: 99%

Genetic analysis using targeted exome sequencing of 53 Vietnamese children with developmental and epileptic encephalopathies

Hieu

Thu

Ngan

et al. 2022

American J of Med Genetics Pt A

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“…Intriguingly, cases have been increasingly reported of females with heterozygous de novo SMC1A pathogenic variants, mostly loss-of-function mutations (LOFs). These variants are associated with a more severe clinical phenotype of developmental and epileptic encephalopathy (DEE), a devastating form of early onset intractable epilepsy beginning in infancy and associated with global developmental delay, cognitive dysfunction, and ongoing epileptiform activity [ 9 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Most reported cases did not show significant brain MRI abnormalities, but cases with holoprosencephaly have been reported [ 15 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Phenotypes and Genotypes in Patients with SMC1A-Related Developmental and Epileptic Encephalopathy

Bozarth

Lopez

et al. 2023

Genes

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The X-linked SMC1A gene encodes a core subunit of the cohesin complex that plays a pivotal role in genome organization and gene regulation. Pathogenic variants in SMC1A are often dominant-negative and cause Cornelia de Lange syndrome (CdLS) with growth retardation and typical facial features; however, rare SMC1A variants cause a developmental and epileptic encephalopathy (DEE) with intractable early-onset epilepsy that is absent in CdLS. Unlike the male-to-female ratio of 1:2 in those with CdLS associated with dominant-negative SMC1A variants, SMC1A-DEE loss-of-function (LOF) variants are found exclusively in females due to presumed lethality in males. It is unclear how different SMC1A variants cause CdLS or DEE. Here, we report on phenotypes and genotypes of three females with DEE and de novo SMC1A variants, including a novel splice-site variant. We also summarize 41 known SMC1A-DEE variants to characterize common and patient-specific features. Interestingly, compared to 33 LOFs detected throughout the gene, 7/8 non-LOFs are specifically located in the N/C-terminal ATPase head or the central hinge domain, both of which are predicted to affect cohesin assembly, thus mimicking LOFs. Along with the characterization of X-chromosome inactivation (XCI) and SMC1A transcription, these variants strongly suggest that a differential SMC1A dosage effect of SMC1A-DEE variants is closely associated with the manifestation of DEE phenotypes.

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“…Among the differentially expressed genes, egr4 and fosl1a (both upregulated) and fosab and npas4l (both downregulated) are isoforms of immediate-early genes that are known to be regulated by calcium signaling [ 13 , 24 ]. We also detected a high level of overexpression of smc1a , which encodes a cohesin complex protein that is involved in regulating nervous system development [ 57 ]. Some other well-known genes, such as kcnc1a , slc20a2 , slc25a17 , slc25a25b , and slc31a1 , which encode proteins that are involved in transporter activity, showed significant changes in the expression of stim2a −/− larvae ( Figure 10 B).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, these oscillations were blocked by 2-Aminoethoxydiphenyl borate (2-APB), a selective inhibitor of SOCE, suggesting the involvement of STIM molecules [ 72 ]. The smc1a gene is a homologue of human SMC1a that was impaired in a patient with Cornelia de Lange, a cohesinopathy that is characterized by the early manifestation of intractable epilepsy [ 57 ]. Our data suggest diverse roles of Stim2 isoforms in the zebrafish brain that might be involved in the maintenance of neuronal SOCE and the regulation of neuronal activity and genetic programs.…”

Section: Discussionmentioning

confidence: 99%

Knockout of stim2a Increases Calcium Oscillations in Neurons and Induces Hyperactive-Like Phenotype in Zebrafish Larvae

Gupta

Wasilewska

Palchevska

et al. 2020

IJMS

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Stromal interaction molecule (STIM) proteins play a crucial role in store-operated calcium entry (SOCE) as endoplasmic reticulum Ca2+ sensors. In neurons, STIM2 was shown to have distinct functions from STIM1. However, its role in brain activity and behavior was not fully elucidated. The present study analyzed behavior in zebrafish (Danio rerio) that lacked stim2a. The mutant animals had no morphological abnormalities and were fertile. RNA-sequencing revealed alterations of the expression of transcription factor genes and several members of the calcium toolkit. Neuronal Ca2+ activity was measured in vivo in neurons that expressed the GCaMP5G sensor. Optic tectum neurons in stim2a−/− fish had more frequent Ca2+ signal oscillations compared with neurons in wildtype (WT) fish. We detected an increase in activity during the visual–motor response test, an increase in thigmotaxis in the open field test, and the disruption of phototaxis in the dark/light preference test in stim2a−/− mutants compared with WT. Both groups of animals reacted to glutamate and pentylenetetrazol with an increase in activity during the visual–motor response test, with no major differences between groups. Altogether, our results suggest that the hyperactive-like phenotype of stim2a−/− mutant zebrafish is caused by the dysregulation of Ca2+ homeostasis and signaling.

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A novel nonsense SMC1A mutation in a patient with intractable epilepsy and cardiac malformation

Cited by 11 publications

References 20 publications

Genetic analysis using targeted exome sequencing of 53 Vietnamese children with developmental and epileptic encephalopathies

Genetic analysis using targeted exome sequencing of 53 Vietnamese children with developmental and epileptic encephalopathies

Phenotypes and Genotypes in Patients with SMC1A-Related Developmental and Epileptic Encephalopathy

Knockout of stim2a Increases Calcium Oscillations in Neurons and Induces Hyperactive-Like Phenotype in Zebrafish Larvae

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