Characterization of a rare Unverricht–Lundborg disease mutation

Duarte, Ana Patrícia; Ribeiro, Diogo; Chaves, João; Amaral, Olga

doi:10.1016/j.ymgmr.2015.07.005

Cited by 9 publications

(9 citation statements)

References 21 publications

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“…At least in the patient fibroblasts, the normal transcript is also generated and normal CSTB protein is expressed, although at lower levels than in control cells ( Figure 2 C). This raises the possibility that the cause of the disease in the patient could be the combined effect of the reduced levels of the CSTB protein and the production of a truncated protein that possibly exerts a toxic or dominant negative role [ 23 ], as was evidenced for other CSTB mutant proteins [ 31 , 32 ]. It is described that CSTB mutants that affect protein sequence are prone to aggregate in cells, even though it is unclear whether protein misfolding and aggregation is responsible for augmenting progression of the disease and neurodegenerative changes, or whether it is the lack of the protein’s function, or a combination of both [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, our group described a Portuguese ULD patient who is homozygous for a new synonymous mutation (c.66G>A; p.Q22Q) which leads to mis-splicing of CSTB pre-mRNA, and, subsequently reported the mislocalization of the resulting mutant protein [ 22 , 23 ]. Two transcripts were found in the patient-derived fibroblasts: a normal transcript with the synonymous G>A change at the last nucleotide of exon 1, and a mutant one including 354 bp of intron 1 due to the activation of a cryptic 5′ss, which is expected to result in the production of an abnormal peptide with a premature truncation.…”

Section: Introductionmentioning

confidence: 99%

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Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy

Matos¹,

Duarte²,

Ribeiro³

et al. 2018

Genes

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Unverricht-Lundborg disease (ULD) is a common form of progressive myoclonic epilepsy caused by mutations in the cystatin B gene (CSTB) that encodes an inhibitor of several lysosomal cathepsins. Presently, only pharmacological treatment and psychosocial support are available for ULD patients. To overcome the pathogenic effect of the ULD splicing mutation c.66G>A (exon 1), we investigated whether an antisense oligonucleotide therapeutic strategy could correct the defect in patient cells. A specific locked nucleic acid (LNA) antisense oligonucleotide was designed to block a cryptic 5′ss in intron 1. Overall, this approach allowed the restoration of the normal splicing pattern. Furthermore, the recovery was both sequence and dose-specific. In general, this work provides a proof of principle on the correction of a CSTB gene defect causing ULD through a mutation-specific antisense therapy. It adds evidence to the feasibility of this approach, joining the many studies that are paving the way for translating antisense technology into the clinical practice. The insights detailed herein make mutation-based therapy a clear candidate for personalized treatment of ULD patients, encouraging similar investigations into other genetic diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy

Matos¹,

Duarte²,

Ribeiro³

et al. 2018

Genes

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“…Cystatin B gene mutations cause ULD, a rare form of PME. 14 Mutation of the nuclear lamin gene LMNB2 causes PME with early ataxia. 15 CLN6 mutation is reported to cause NCLs, another form of PME.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel CACNA1A mutation in a Chinese family with autosomal recessive progressive myoclonic epilepsy

Y¹,

Wang²,

Liu³

et al. 2017

NDT

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BackgroundProgressive myoclonic epilepsy (PME) is a heterogeneous neurodegenerative disorder, which is commonly manifested with refractory seizures and neurologic deterioration. The prognosis of PME is poor, so early diagnosis of PME is critical. The aim of our study is to identify the novel pathogenic gene in a Chinese family with PME, which may be helpful in future.Subjects and methodsA three-generation consanguineous Chinese Han family with PME was recruited. A novel homozygous variant was identified by the genetic technique of exome sequencing and certificated by Sanger sequencing and functional prediction.ResultsA novel homozygous variant, c.6975_6976insCAG, in the CACNA1A was identified in the PME family. The novel variant encoding the alpha-1A subunit of the calcium channel Cav2.1 was found in two siblings in the Chinese family and was absent in 50 normal controls. Our research indicates that the homozygous c.6975_6976insCAG might be the pathogenic mutation for PME.ConclusionAs a molecular diagnostic strategy, our research explores the mutation gene spectrum of PME and has resulted in significant predictions for genetic counseling.

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“…Конечным результатом является выраженный дисбаланс между белка-ми и срыв внутриклеточной регуляции [5].…”

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Unverricht-Lundborg disease in an adult female patient: a clinical case

Карлов¹,

Жидкова²,

Mishina³

et al. 2018

RJTAO

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Прогрессирующие миоклонус-эпилепсии -клиниче-ски и этиологически гетерогенные генетические заболева-ния, характеризующиеся миоклонусом, генерализованны-ми тонико-клоническими приступами и прогрессирующи-ми церебральными расстройствами, главные из которых -атаксия и деменция. Преобладание миоклоний с прогресси-рующим течением объясняет объединение не менее 15 но-зологических форм, относимых к миоклонус-эпилепсии, в одну группу. Однако, по данным Марсельской группы со-гласования, абсолютное большинство составляют пять за-болеваний, а именно: болезнь Унферрихта-Лундборга (БУЛ), болезнь Лафора, синдром MERRF, нейрональный цероидный липофусциноз и сиалидоз [1]. Клонус (от греч. clonos) -это движение. Миоклонус -это аритмичные/рит-мичные, непроизвольные быстрые кратковременные мы-шечные сокращения, обусловленные вовлечением в пато-логический процесс центральной нервной системы (пози-тивный миоклонус). Наряду с этим различают негативный миоклонус, реализуемый кратковременным выключением мышечного тонуса. В основе заболевания лежат генетиче-ские факторы, в частности нарушения в митохондриальном геноме, либо наследственные болезни обмена [2].

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Characterization of a rare Unverricht–Lundborg disease mutation

Cited by 9 publications

References 21 publications

Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy

Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy

Identification of a novel CACNA1A mutation in a Chinese family with autosomal recessive progressive myoclonic epilepsy

Unverricht-Lundborg disease in an adult female patient: a clinical case

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