DSP

Gene Facts

• HGNC Symbol: DSP (HGNC:3052)
• HGNC Name: desmoplakin
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: KPPS2, PPKS2, DPI, DPII
• %HI: 12.87
• pLI: 1
• LOEUF: 0.44
• Cytoband: 6p24.3
• Genomic Coordinates:

  GRCh37/hg19:	chr6:7541904-7586947
  GRCh38/hg38:	chr6:7541671-7586714

• MANE Select Transcript: NM_004415.4 ENST00000379802.8
• Function: Major high molecular weight protein of desmosomes. Regulates profibrotic gene expression in cardiomyocytes via activation of the MAPK14/p38 MAPK signaling cascade and increase in TGFB1 protein abundance (By similarity). {ECO:0000250|UniProtKB:F1LMV6}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-8684
• ClinGen Curation ID: CCID:007039
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 10/12/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Dilated Cardiomyopathy

HI Evidence

• PUBMED: 31514951
  Gigli M et al. genotyped 487 patients with dilated cardiomyopathy using next-generation sequencing. Among these patients, 14 had variants in DSP with 10 of these being frameshift or nonsense variants. Among these 10 variants, 4 occurred >50 bp upstream of the penultimate exon and thus predicted to trigger nonsense-mediated decay of transcripts.
• PUBMED: 27532257
  Walsh R et al. (2017) analyzed 7,855 clinical cardiomyopathy cases for sequencing data for 20 hypertrophic cardiomyopathy genes, 48 dilated cardiomyopathy genes, and 8 arrhythmic right ventricular dysplasia genes. Among these patients, 8 had dilated cardiomyopathy and 16 had arrhythmic right ventricular dysplasia/cardiomyopathy associated with nonsense/canonical splice site/frameshift DSP variants located >50 bp upstream of the 3’ end of the penultimate exon. All of these variants are predicted to be in both the DSP I and II isoforms except for one reported case of dilated cardiomyopathy and 4 cases of arrhythmic right ventricular dysplasia/cardiomyopathy.
• PUBMED: 24503780
  Pugh TJ et al. (2014) surveyed 766 patients with dilated cardiomyopathy and identified 3 patients with a clinical diagnosis and family history of dilated cardiomyopathy associated with DSP variants. One patient had a DSP frameshift variant in exon 20 of 24, another had a nonsense variant in exon 5 of 20, and a third had a canonical slice site variant at the 3’ end of exon 7 that was shown by PCR analysis to cause inclusion of intron 7 into the variant mRNA, leading to a downstream premature termination codon (PMID: 10594734). All variants are predicted to trigger nonsense-mediated decay.
• PUBMED: 23810894
  te Riele A et al. (2013) assessed 69 patients harboring arrhythmic right ventricular dysplasia/cardiomyopathy pathogenic mutations. Among patients with disease associated with DSP variants, 2 carried nonsense mutations (neither in the penultimate or ultimate exon) predicted to cause nonsense-mediated decay of transcripts in both DSP I and II transcripts.
• PUBMED: 20716751
  Elliot P et al. (2010) screened 100 unrelated patients with dilated cardiomyopathy for variants in plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. Loss of function variants in DSP were identified in two patients. One variant was a canonical splice site variant at the 3’ end of exon 15 of 24 that is predicted to cause abnormal and the other variant a frameshift variant in exon 19.
• PUBMED: 31319917
  DeWitt E et al. (2020) described pediatric and adolescent patients with arrhythmogenic cardiomyopathy. Among 32 patients presenting with this disease, 5 carried frameshift or nonsense variants in DSP that were predicted to cause nonsense-mediated decay of transcripts.

• HI Evidence Comments: This curation focused on the association between DSP loss-of-function variants and autosomal dominant cardiomyopathy. However, DSP is associated with multiple phenotypes, which are heterogeneous, often overlapping, and include skin (e.g., skin fragility, keratoderma, and epidermolysis bullosa), hair (e.g., woolly hair and alopecia), tooth (e.g., tooth agenesis), and heart abnormalities (e.g., arrhythmias and cardiomyopathies). These phenotypes include autosomal dominant arrhythmogenic right ventricular dysplasia (OMIM # 607450), autosomal recessive dilated cardiomyopathy with woolly hair and keratoderma (OMIM # 605676), autosomal dominant dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (OMIM # 615821), autosomal recessive acantholytic epidermolysis bullosa (OMIM # 609638), autosomal dominant striated keratosis palmoplantaris (OMIM # 612908), and autosomal recessive skin fragility-woolly hair syndrome (OMIM # 607655). Notably, there is evidence that haploinsufficiency may be associated with at least some of these phenotypes (PMID: 19178614, 25227139, 29633331) in addition to cardiomyopathy. Furthermore, DSP is expressed in two major isoforms generated by alternative splicing of exon 23 of 24: DSP I and DSP II. DSP I is the only isoform expressed in the heart, while both DSP I and II are expressed in other tissues, such as the skin (PMID: 23137101). Therefore, loss-of-function variants identified in exon 23, which is the penultimate exon, should be closely considered before nonsense-mediated decay will occur in transcripts of all isoforms. Evidence suggests haploinsufficiency of the DSP I isoform, rather than all isoforms, may be associated with certain DSP-related disorders (PMID: 25227139).

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity