Identification of a Novel Homozygous Splice-Site Mutation in SCARB2 that Causes Progressive Myoclonus Epilepsy with or without Renal Failure

He, J.; Lin, Han; Li, Jinjing; Su, Hui-Zhen; Wang, Danni; Lin, Ye; Wang, Ning; Chen, Wan‐Jin

doi:10.4103/0366-6999.235113

Cited by 4 publications

(1 citation statement)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tonin et al identified a newly discovered synonymous c.363A>G (Gly82Gly) mutation in the β-glucosidase (GBA) gene in a type 3 Gaucher disease patient that causes the loss of an exon splicing enhancer (17). He et al revealed a novel c.995-1G>A homozygous splicing mutation in the SCARB2 gene in two PME patients that leads to loss of function of the SCARB2 protein (18).…”

Section: Discussionmentioning

confidence: 99%

An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

Sun

et al. 2020

Oncol Rep

View full text Add to dashboard Cite

An aberrant elongated tract of glutamine residues (polyQ) in proteins induces multiple diseases treated in the clinic. In our previous study of progressive myoclonic epilepsy (PME), using whole-exome sequencing, a mutant Cav2.1 protein with an aberrant elongated polyQ tract was identified in PME patients. To investigate the molecular mechanism and cell biology of this aberrant elongated polyQ tract, wild-type Cav2.1 with 13 polyQ repeats (Cav2.1 wt-Q13) and mutant-type Cav2.1 with 26 polyQ repeats (Cav2.1 mt-Q26) were prepared and introduced into human SH-SY5Y neuroblastoma cells. Using a WST-1 assay, it was revealed that Cav2.1 mt-Q26 markedly suppressed the proliferation of the SH-SY5Y cells, a result not observed for the Cav2.1 wt-Q13-transfected cells. It was also revealed that Cav2.1 mt and its truncated molecules suppressed cell proliferation by inducing apoptosis rather than arresting the cell cycle. Further investigations indicated a nuclear translocation phenomenon associated with the Cav2.1 mt molecules. Mechanistically, it was revealed that the Cav2.1 mt molecules activated the Bcl-2/Bax, caspase-3 and poly ADP-ribose polymerase (PARP) apoptotic pathways. The present study may provide new insights for interpreting the pathogenesis of PME and the relationship among polyQ, CACNA1A gene mutations and PME.

show abstract

Section: Discussionmentioning

confidence: 99%

An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

Sun

et al. 2020

Oncol Rep

View full text Add to dashboard Cite

show abstract

Myoclonus‐Ataxia Syndromes: A Diagnostic Approach

Rossi

Veen

Merello

et al. 2020

Movement Disord Clin Pract

View full text Add to dashboard Cite

Background Background: A myriad of disorders combine myoclonus and ataxia. Most causes are genetic and an increasing number of genes are being associated with myoclonus-ataxia syndromes (MAS), due to recent advances in genetic techniques. A proper etiologic diagnosis of MAS is clinically relevant, given the consequences for genetic counseling, treatment, and prognosis. Objectives Objectives: To review the causes of MAS and to propose a diagnostic algorithm. Methods Methods: A comprehensive and structured literature search following PRISMA criteria was conducted to identify those disorders that may combine myoclonus with ataxia. Results Results: A total of 135 causes of combined myoclonus and ataxia were identified, of which 30 were charted as the main causes of MAS. These include four acquired entities: opsoclonus-myoclonus-ataxia syndrome, celiac disease, multiple system atrophy, and sporadic prion diseases. The distinction between progressive myoclonus epilepsy and progressive myoclonus ataxia poses one of the main diagnostic dilemmas. Conclusions Conclusions: Diagnostic algorithms for pediatric and adult patients, based on clinical manifestations including epilepsy, are proposed to guide the differential diagnosis and corresponding work-up of the most important and frequent causes of MAS. A list of genes associated with MAS to guide genetic testing strategies is provided. Priority should be given to diagnose or exclude acquired or treatable disorders.

show abstract

Genotype–Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review

et al. 2022

View full text Add to dashboard Cite

Background Biallelic pathogenic variants in the SCARB2 gene have been associated with action myoclonus-renal failure (AMRF) syndrome. Even though SCARB2 associated phenotype has been reported to include typical neurological characteristics, depending on the localization and the feature of the pathogenic variants, clinical course and the presentations have been shown to differ. Case presentation Whole exome sequencing (WES) analysis revealed a homozygous truncating variant (p.N45MfsX88) in SCARB2 gene in the index case, and subsequent sanger sequencing analysis validated the variant in all affected family members from a Turkish family with the clinical characteristics associated with AMRF and related disorders. Intrafamilial clinical heterogeneity with common features including dysarthria, tremor and proteinuria, and distinct features such as peripheral neuropathy (PNP), myoclonus and seizures between the affected cases, was observed in the family. In-depth literature review enabled the detailed investigation of the reported variants associated with AMRF and suggested that while the type of the variant did not have a major impact on the course of the clinical characteristics, only the C terminal localization of the pathogenic variant significantly affected the clinical presentation, particularly the age at onset (AO) of the disease. Conclusions In this study we showed that biallelic SCARB2 pathogenic variants might cause a spectrum of common and distinct features associated with AMRF. Of those features while the common features include myoclonus (100%), ataxia (96%), tonic clonic seizures (82%), dysarthria (68%), tremor (65%), and renal impairment (62%), the uncommon features involve PNP (17%), hearing loss (6.8%), and cognitive impairment (13.7%). AO has been found to be significantly higher in the carriers of the p.G462DfsX34 pathogenic variant. SCARB2 pathogenic variants have not been only implicated in AMRF but also in the pathogenesis of Parkinson’s disease (PD) and Gaucher disease (GD), suggesting the importance of genetic and functional studies in the clinical and the diagnostic settings. Given the proven role of SCARB2 gene in the pathogenesis of AMRF, PD and GD with a wide spectrum of clinical symptoms, investigation of the possible modifiers, such as progranulin and HSP7, has a great importance.

show abstract

Identification of a Novel Homozygous Splice-Site Mutation in SCARB2 that Causes Progressive Myoclonus Epilepsy with or without Renal Failure

Cited by 4 publications

References 39 publications

An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

Myoclonus‐Ataxia Syndromes: A Diagnostic Approach

Genotype–Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review

Contact Info

Product

Resources

About