ε-Sarcoglycan: Unraveling the Myoclonus-Dystonia Gene

Cazurro-Gutiérrez, Ana; Marcé‐Grau, Anna; Correa‐Vela, Marta; Salazar, Ainara; Vanegas, Maria; Macaya, Alfons; Bayés, Àlex; Pérez‐Dueñas, Belén

doi:10.1007/s12035-021-02391-0

Cited by 8 publications

(6 citation statements)

References 78 publications

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“…However, whether SGCE plays a role in MD manifestation has been debated. On the one hand, animal studies have shown that knocking out this gene causes myoclonus, motor coordination deficits, and depression-like behaviour (Cazurro-Gutiérrez et al, 2021) which is consistent with the lower expression levels reported by GTEx. On the other hand, a similar frequency of MD has been reported in SCGE mutated and wild-type myoclonus dystonia patients (Kim et al, 2017).…”

Section: Discussionsupporting

confidence: 82%

“…The brain frontal cortex, hypothalamus, pituitary and brain cerebellar hemisphere have common findings between PICS and both colocalization tools. MD and myclonus-dystonia are usually comorbid, and their association has typically been studied in relation to SGCE mutation and its potential pleiotropic effect ( Peall et al, 2013 ; Kim et al, 2017 ; Cazurro-Gutiérrez et al, 2021 ). However, whether SGCE plays a role in MD manifestation has been debated.…”

Section: Discussionmentioning

confidence: 99%

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Benchmarking post-GWAS analysis tools in major depression: Challenges and implications

Pérez-Granado

Piñero²,

Furlong³

2022

Front. Genet.

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Our knowledge of complex disorders has increased in the last years thanks to the identification of genetic variants (GVs) significantly associated with disease phenotypes by genome-wide association studies (GWAS). However, we do not understand yet how these GVs functionally impact disease pathogenesis or their underlying biological mechanisms. Among the multiple post-GWAS methods available, fine-mapping and colocalization approaches are commonly used to identify causal GVs, meaning those with a biological effect on the trait, and their functional effects. Despite the variety of post-GWAS tools available, there is no guideline for method eligibility or validity, even though these methods work under different assumptions when accounting for linkage disequilibrium and integrating molecular annotation data. Moreover, there is no benchmarking of the available tools. In this context, we have applied two different fine-mapping and colocalization methods to the same GWAS on major depression (MD) and expression quantitative trait loci (eQTL) datasets. Our goal is to perform a systematic comparison of the results obtained by the different tools. To that end, we have evaluated their results at different levels: fine-mapped and colocalizing GVs, their target genes and tissue specificity according to gene expression information, as well as the biological processes in which they are involved. Our findings highlight the importance of fine-mapping as a key step for subsequent analysis. Notably, the colocalizing variants, altered genes and targeted tissues differed between methods, even regarding their biological implications. This contribution illustrates an important issue in post-GWAS analysis with relevant consequences on the use of GWAS results for elucidation of disease pathobiology, drug target prioritization and biomarker discovery.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Benchmarking post-GWAS analysis tools in major depression: Challenges and implications

Pérez-Granado

Piñero²,

Furlong³

2022

Front. Genet.

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“…The SGCE variant NM_003919.3:c.1046_1047del:p.(Arg349Lysfs * 29), predicted by VarSome as likely pathogenic, was identified by MyoCap and by exome sequencing in the proband but not in his brother or sister. Dominant SGCE mutations are a reported cause of myoclonus–dystonia, a phenotype not compatible with that seen in our patients ( 24 ). The identified frameshift variant affects an alternatively spliced exon and was according to RNAseq only present in ~25% of SGCE transcripts in the proband’s muscle biopsy.…”

Section: Resultscontrasting

confidence: 71%

Extension of the DNAJB2a isoform in a dominant neuromyopathy family

Sarparanta

Jonson

Reimann

et al. 2023

Human Molecular Genetics

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Recessive mutations in the DNAJB2 gene, encoding the J-domain cochaperones DNAJB2a and DNAJB2b, have previously been reported as the genetic cause of progressive peripheral neuropathies, rarely involving pyramidal signs, parkinsonism, and myopathy. We describe here a family with the first dominantly acting DNAJB2 mutation resulting in a late-onset neuromyopathy phenotype. The c.832 T > G p.(*278Glyext*83) mutation abolishes the stop codon of the DNAJB2a isoform resulting in a C-terminal extension of the protein, with no direct effect predicted on the DNAJB2b isoform of the protein. Analysis of the muscle biopsy showed reduction of both protein isoforms. In functional studies, the mutant protein mislocalized to the endoplasmic reticulum due to a transmembrane helix in the C-terminal extension. The mutant protein underwent rapid proteasomal degradation and also increased the turnover of co-expressed wild-type DNAJB2a, potentially explaining the reduced protein amount in the patient muscle tissue. In line with this dominant negative effect, both wild-type and mutant DNAJB2a were shown to form polydisperse oligomers.

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“…Genotype–phenotype relationships are often complex and incompletely understood in genetic movement disorders such as PRRT2 ‐related disorders [ 57 , 108 ] and SGCE ‐related MDS. [ 109 ] A common bottleneck is the limited number of cases available for the study of each genetically‐defined condition. There may also be a publication bias toward unusual manifestations of these disorders, resulting in the overrepresentation of atypical cases in the literature.…”

Section: Common Themes and Prospectsmentioning

confidence: 99%

Translating Genetic Discovery into a Mechanistic Understanding of Pediatric Movement Disorders: Lessons from Genetic Dystonias and Related Disorders

Lin

2022

Advanced Genetics

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The era of next‐generation sequencing has increased the pace of gene discovery in the field of pediatric movement disorders. Following the identification of novel disease‐causing genes, several studies have aimed to link the molecular and clinical aspects of these disorders. This perspective presents the developing stories of several childhood‐onset movement disorders, including paroxysmal kinesigenic dyskinesia, myoclonus‐dystonia syndrome, and other monogenic dystonias. These stories illustrate how gene discovery helps focus the research efforts of scientists trying to understand the mechanisms of disease. The genetic diagnosis of these clinical syndromes also helps clarify the associated phenotypic spectra and aids the search for additional disease‐causing genes. Collectively, the findings of previous studies have led to increased recognition of the role of the cerebellum in the physiology and pathophysiology of motor control—a common theme in many pediatric movement disorders. To fully exploit the genetic information garnered in the clinical and research arenas, it is crucial that corresponding multi‐omics analyses and functional studies also be performed at scale. Hopefully, these integrated efforts will provide us with a more comprehensive understanding of the genetic and neurobiological bases of movement disorders in childhood.

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ε-Sarcoglycan: Unraveling the Myoclonus-Dystonia Gene

Cited by 8 publications

References 78 publications

Benchmarking post-GWAS analysis tools in major depression: Challenges and implications

Benchmarking post-GWAS analysis tools in major depression: Challenges and implications

Extension of the DNAJB2a isoform in a dominant neuromyopathy family

Translating Genetic Discovery into a Mechanistic Understanding of Pediatric Movement Disorders: Lessons from Genetic Dystonias and Related Disorders

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