ClinVar

In a 17-year-old girl with woolly hair, skin fragility, and disabling palmoplantar keratoderma (DCWHK; 605676), Whittock et al. (2002) reported compound heterozygosity for mutations in the DSP gene: a c.7096C-T transition in exon 24 that resulted in an arg2366-to-cys (R2366C) amino acid change, and a c.1990C-T transition in exon 15 that resulted in a gln664-to-ter amino acid change (Q664X; 125647.0007). The Q664X allele resulted in nonsense-mediated mRNA decay and only the R2366C DSP gene product was expressed, resulting in a severe keratoderma phenotype. The R2366C change occurred within the intermediate filament carboxy B domain. Specifically, this changed a charged residue at position 22 of the third 38-amino acid repeat. This sequence is highly conserved among the other plakin molecules plectin (601282), bullous pemphigoid antigen-1 (113810), and epiplakin (607553), with a consensus motif of GXRXLE (Ruhrberg and Watt, 1997; Fujiwara et al., 2001). This residue may be involved with the bundle formation that binds to intermediate filament proteins. The substitution of a cysteine would be expected to affect intrachain and/or interchain disulfide bonding, thus changing the tertiary structure of the C-terminal domain. Although the patient had no apparent cardiac anomalies, the authors considered her to be at risk for dilated left ventricular cardiomyopathy.