ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000006.11) (NC_000006.12)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
15941723 Bauce et al (2005) identified DSP mutations in 38 subjects from 4 families in whom the proband all had AVRC. Unaffected mutation carriers were found in all families. Three families had missense mutations that were predicted to either alter confirmation of the protein or its interaction with other proteins. One family had a splicing mutation that resulted in exon 4 skipping and was predicted to result in a truncated protein. Whether that led to NMD or expression of an abnormal protein is not known, as no functional studies were performed. There were members of this family with cardiac features who did not fulfill criteria for AVRC diagnosis, suggesting incomplete penetrance.
23137101 Rasmussen et al (2013) described DSP gene mutations in three families with autosomal dominant arrythmogenic right ventricular dysplasia (AVRC) and one family with a child with recessive Carvajal syndrome. The DSP gene encodes two isoforms. Heart tissue expresses only the DSP1 isoform, while other tissues, such as skin, express both DSP1 and DSP2. In one family with AVRC, the observed mutation was a nonsense mutation that was demonstrated by Western blot and qRT-PCR to result in vastly reduced expression of DSP1 only. The authors suggest that the ARVC phenotype in this family may be a result of haploinsufficiency. They also speculate that because there was an unaffected mutation carrier in this family, another unidentified mutation may be possible. Another family with an in-frame deletion had unaffected mutation carriers, as well as affected carriers. The affected individuals all also had a mutation in PKP2, another gene associated with AVRC, however, individual III-1 also had both DSP and PKP2 mutations and was asymptomatic. The in-frame deletion reduced the expression of both DSP1/2 isoforms, and the authors suggest the possibility that the mutant PKP2 may allow for the incorporation of mutant DSP1 isoforms into the desmosome, whereas the isolated DSP mutation carriers do not have this incorporation. The functional studies of the third AVRC family did not demonstrate an effect of the mutation on protein expression, suggesting an alternative mechanism for their disease. The authors hypothesize that haploinsufficiency of DSP may be necessary but not sufficient to result in ARVC. Indeed, Uzumcu et al (PMID: 16467215) describe a consanguineous family in which the healthy parents both carry a nonsense mutation that affects only the DSP1 isoform. Neither had cardiac or skin/hair issues.

Haploinsufficiency phenotype comments:

The desmosomal cardiomyopathies are often associated with a complex mode of inheritance and a highly variable pattern of protein expression. AR inheritance form mutations are often ?loss of function? mutations and AD forms are known to occur. However, there is no clear evidence that they are due to haploinsufficiency; dominant negative effect appears to be the more likely mechanism of pathogenicity in these cases. Furthermore, whole gene deletions have not been reported in the literature. At most, haploinsuffiency may result in skin manifestations (hereditary palmoplantar keratoderma) or may contribute in a multifactorial manner to susceptibility to heart disease

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity