Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma [published erratum appears in Hum Mol Genet 1999 May;8(5):943]

Abstract

Desmosomes are highly organized intercellular adhesive junctions that are particularly prominent in epidermis and other tissues experiencing mechanical stress. Desmoplakin, a constitutive component of the desmosomal plaque, is the most abundant protein present in such junctions and plays a critical role in linking the intermediate filament network to the plasma membrane in these tissues. Here we report the first mutation in the gene encoding desmoplakin. The identified mutation, resulting in a null allele and haploinsufficiency, was observed in genomic DNA from a kindred with the dominantly inherited skin disorder, striate palmoplantar keratoderma. Affected individuals had a linear pattern of skin thickening on the fingers and palms and circumscribed areas of skin thickening on the soles. Affected skin demonstrated loosening of intercellular connections, disruption of desmosome-keratin intermediate filament interactions and a proportion of rudimentary desmosomal structures. The disorder mapped to chromosome 6p21 with a maximum lod score of 10.67. The mutation was a heterozygous C-->T transition in exon 4 of the desmoplakin gene and predicted a premature termination codon in the N-terminal region of the peptide. This is the first reported mutation of desmo-plakin and also the first inherited skin disorder in which haploinsufficiency of a structural component has been implicated. It identifies dosage of desmoplakin as critical in maintaining epidermal integrity.

Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma

“…Haploinsufficiency has also been implicated as the cause of autosomal dominance for SPPK caused by mutation in the desmoplakin gene. 8,9 The reason for the preponderance of SPPK mutations in the DSG1 gene rather than in another desmosomal cadherin suggests that desmoglein 1 is a key protein in desmosome GGTAAT?GGTAT frameshift (PTC+11aa) extracellular domain 4 (EC4) a Numbering of the amino acids refers to the human DSG1 peptide sequence. b Numbering of the nucleotides refers to the human DSG1 cDNA sequence (EMBL X56654) in which the ATG coding for methionine at nt 78 in the sequence ATGGACTGG is presumed to be the initiation codon, with the first nucleotide of this ATG codon as 1.…”

“…Striate palmoplantar keratoderma (SPPK; MIM 148700) is one of a group of skin diseases where there is thickening of the skin on the palms and soles, 4,5 this particular disease being characterised by longitudinal hyperkeratotic lesions on the palms, running the length of each finger. Two types of SPPK have been reported to date, one mapping to chromosome 18q12.1 6 where the desmosomal cadherins map 7 and one on 6p21 8 where the desmoplakin gene is found, 7 and mutations have been found in both the desmoplakin gene, 8,9 and in a desmosomal cadherin, desmoglein. 10 It is thought that in this disease, incorrect desmosomal function results in hyperkeratotic lesions in those regions of the body where desmosome function is most necessary.…”

Diseases of epidermal keratins and their linker proteins

“…Mutations in the desmoglein 1 gene (DSG1) in an inherited skin disorder were first identified in a three-generation Dutch family with striate palmoplantar keratoderma (i.e. similar phenotype to the cases reported by Armstrong et al, [69] with DSP haploinsuffficiency) who had a heterozygous acceptor splice site mutation, IVS2-1G>A, in the DSG1 gene [77]. This mutation occurs within the prosequence of DSG1 but results in skipping of exons 2-4 and generates a peptide that is only 25 amino acids in length.…”

“…Specifically, heterozygous mutations in PKP2 represent the major cause of familial arrhythmogenic ventricular cardiomyopathy, an autosomal dominant condition characterized by ventricular arrhythmias, syncope and sudden death, usually precipitated by exertion [68] Desmoplakin Mutations -A Spectrum of Skin, Hair and Heart Phenotypes Evidence for a primary inherited abnormality of DSP emerged from a linkage study that mapped an autosomal dominant pedigree with striate palmoplantar keratoderma ( Figure 6A) to 6p24, a locus containing the DSP gene [69]. Microscopy of palmar skin showed massive hyperkeratosis along with dysadhesion between suprabasal keratinocytes and abnormal cellcell and cell membrane-cytoskeletal adhesion ( Figure 6B and C) and screening of genomic DNA identified a heterozygous nonsense mutation, p.Q331X, in the DSP gene [69]. Thus, the keratoderma in this family was due to DSP haploinsufficiency, demonstrating that 50 percent of normal DSP levels are sufficient for normal epidermal functioning in nonpalmoplantar skin but insufficient for withstanding trauma to the palms and soles.…”

Etiopathogenesis of arrhythmogenic right ventricular cardiomyopathy

“…It is the key protein of inner-most desmosomal plaque, serving as an attachment site for cytoplasmic intermediate filaments apart from playing a role in desmosomal assembly, stability and regulation and affecting the modeling of tissue architecture during embryogenesis (Gallicano et al 1998). Mutations in desmoplakin have been reported for various disorders of skin and heart, which are striate palmoplantar keratoderma II (SPPK2) (Armstrong et al 1999), dilated cardiomyopathy with woolly hair and keratoderma (DCWHK) (Norgett et al 2000), skin fragility-woolly hair syndrome (SFWHS) (Whittock et al 2002) and familial ARVC8.…”