Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction

Abstract

Genetic variants in gene-encoding proteins involved in cell–cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics. The genotype–phenotype correlation, however, remains poorly understood. By providing an overview of variants that are assessed for a functional protein pathology, we show that this number (n = 115) is low compared to the number of variants that are assessed by in silico algorithms (>5000). As expected, there is a mismatch between the prediction of variant pathogenicity and the prediction of the functional effect compared to the real functional evidence. Aiding to improve genotype–phenotype correlations, we separate variants into ‘protein reducing’ or ‘altered protein’ variants and provide general conclusions about the skin and heart phenotype involved. We conclude by stipulating that adequate prognoses can only be given, and targeted therapies can only be designed, upon full knowledge of the protein pathology through functional investigation.

Advanced searching for hypertrophic cardiomyopathy heritability in real practice tomorrow

“…KLHL24 encodes the Kelch-like protein 24 that is commonly expressed in the skin and heart and involved in intercellular compliance networks. Kelch-like protein 24 regulates ubiquitination and subsequent proteasome degradation of keratins in keratinocytes and desmin in cardiomyocytes; the dysregulation of this process can result in both an excessive degradation and, on the contrary, an accumulation of intermediate filament proteins ( 63 ). Pathogenic variants in KLHL24 gene may cause solitary skin (MIM #617294) or heart disorders (HCM, MIM #620236) ( 64 ), as well as combined so-called cardiocutaneous syndromes (MIM #617294).…”

“…Causal variants in KLHL24 are rare in the general population, and establishing their pathogenicity is challenging. A summary of the functional impact of eight KLHL24 variants on protein function has recently been published ( 63 ). Generally, patients with heterozygous gain-of-function variants can develop DCM phenotype with desmin deficiency, meanwhile, HCM with desmin-overload has been determined in patients with homozygous loss-of-function variants.…”

Epidermal growth factor receptor inhibition leads to cellular phenotype correction of DSP‐mutated keratinocytes

“…In skin, DSP is expressed throughout the epidermis, where it anchors the intermediate filaments to the desmosomal architecture at the plasma membrane. Pathogenic variants in the gene DSP encoding DSP cause a wide range of phenotypes, such as skin fragility, woolly hair (WH), palmoplantar keratoderma (PPK), arrhythmogenic/dilated cardiomyopathy (ACM/DCM) or a combination of these 1 . PPK is one of the most frequent symptoms associated with DSP variants.…”

“…A recent literature overview indicated the need for better understanding of DSP variants on RNA and protein to aid the genotype–phenotype correlation, as existing in silico prediction programs do not always predict the actual effect 1 . Here, we described the effect of the DSP variant c.3337C>T; p.(Arg1113*) on mRNA and protein synthesis and its biological effects on keratinocytes of the index patient, clinically affected by PPK, WH and ACM.…”

“…Lesional skin is characterized by loosening of intercellular connections and widening of the intercellular spaces called acantholysis, and keratin intermediate filament retraction towards the nucleus 2,3 . Genotype–phenotype correlations are frequently inconclusive, and recent studies showed that DSP variants often do not behave as predicted 1 …”