Compound heterozygous mutations in desmoplakin associated with skin fragility, follicular hyperkeratosis, alopecia, and nail dystrophy

Bari, Omar; Skillman, Sarah; Lah, Melissa; Haggstrom, Anita N.

doi:10.1111/pde.13498

Cited by 2 publications

(2 citation statements)

References 4 publications

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“…In the DSP gene, only two variants causing PTC have been described in ACM patients [ 11 ] and five in the general population [ 48 ]. Patients carrying DSP: p.R160X had no cardiac dysfunction at the age of examination (8 months old) [ 49 ]. Similarly, in the JUP gene, only one variant has been described in ACM patients [ 11 ] and three in the general population [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Premature Termination Codon in 5′ Region of Desmoplakin and Plakoglobin Genes May Escape Nonsense-Mediated Decay through the Reinitiation of Translation

Vallverdú-Prats

Brugada

Alcalde

2022

IJMS

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Arrhythmogenic cardiomyopathy is a heritable heart disease associated with desmosomal mutations, especially premature termination codon (PTC) variants. It is known that PTC triggers the nonsense-mediated decay (NMD) mechanism. It is also accepted that PTC in the last exon escapes NMD; however, the mechanisms involving NMD escaping in 5′-PTC, such as reinitiation of translation, are less known. The main objective of the present study is to evaluate the likelihood that desmosomal genes carrying 5′-PTC will trigger reinitiation. HL1 cell lines were edited by CRISPR/Cas9 to generate isogenic clones carrying 5′-PTC for each of the five desmosomal genes. The genomic context of the ATG in-frame in the 5′ region of desmosomal genes was evaluated by in silico predictions. The expression levels of the edited genes were assessed by Western blot and real-time PCR. Our results indicate that the 5′-PTC in PKP2, DSG2 and DSC2 acts as a null allele with no expression, whereas in the DSP and JUP gene, N-truncated protein is expressed. In concordance with this, the genomic context of the 5′-region of DSP and JUP presents an ATG in-frame with an optimal context for the reinitiation of translation. Thus, 5′-PTC triggers NMD in the PKP2, DSG2* and DSC2 genes, whereas it may escape NMD through the reinitiation of the translation in DSP and JUP genes, with no major effects on ACM-related gene expression.

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Section: Discussionmentioning

confidence: 99%

Premature Termination Codon in 5′ Region of Desmoplakin and Plakoglobin Genes May Escape Nonsense-Mediated Decay through the Reinitiation of Translation

Vallverdú-Prats

Brugada

Alcalde

2022

IJMS

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“…Mono-allelic dominant mutations in DSP have been associated with known cardiac disorders, like classic ARVC [15] and DCM [2,16], as well as sudden cardiac arrest [17] and sudden cardiac death [18]. Bi-allelic recessive DSP mutations cause Carvajal syndrome (syndromic form of DCM with palmoplantar keratoderma and woolly hair) [19][20][21] and familial nonsyndromic DCM [22]. Moreover, Smith et al proposed that the DSP cardiomyopathy is a distinct form of ACM, characterized by episodic myocardial injury and left ventricular fibrosis along with a high incidence of ventricular arrhythmias that precede systolic dysfunction [23].…”

Section: Introductionmentioning

confidence: 99%

A Novel DSP Truncating Variant in a Family with Episodic Myocardial Injury in the Course of Arrhythmogenic Cardiomyopathy—A Possible Role of a Low Penetrance NLRP3 Variant

Chmielewski

Truszkowska

Kukla³

et al. 2020

Diagnostics

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Mono-allelic dominant mutations in the desmoplakin gene (DSP) have been linked to known cardiac disorders, such as arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy. During the course of DSP cardiomyopathy, episodes of acute myocardial injury may occur. While their mechanisms remain unclear, myocarditis has been postulated as an underlying cause. We report on an adolescent girl with arrhythmogenic biventricular cardiomyopathy and three acute myocarditis-like episodes in whom we found a novel truncating DSP variant accompanied by a known low penetrance R490K variant in the NLRP3. Upon family screening, other carriers of the DSP variant have been identified in whom only mild cardiac abnormalities were found. We hypothesized that the uncommon course of cardiomyopathy in the proband as well as striking discrepancies in the phenotype observed in her family may be explained by the co-existence of her low penetrance genetic autoinflammatory predisposition.

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Compound heterozygous mutations in desmoplakin associated with skin fragility, follicular hyperkeratosis, alopecia, and nail dystrophy

Cited by 2 publications

References 4 publications

Premature Termination Codon in 5′ Region of Desmoplakin and Plakoglobin Genes May Escape Nonsense-Mediated Decay through the Reinitiation of Translation

Premature Termination Codon in 5′ Region of Desmoplakin and Plakoglobin Genes May Escape Nonsense-Mediated Decay through the Reinitiation of Translation

A Novel DSP Truncating Variant in a Family with Episodic Myocardial Injury in the Course of Arrhythmogenic Cardiomyopathy—A Possible Role of a Low Penetrance NLRP3 Variant

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