Other entities represented in this entry:
HGNC Approved Gene Symbol: DSP
SNOMEDCT: 1230026002, 719835006;
Cytogenetic location: 6p24.3 Genomic coordinates (GRCh38): 6:7,541,671-7,586,714 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p24.3 | Arrhythmogenic right ventricular dysplasia 8 | 607450 | Autosomal dominant | 3 |
| Cardiomyopathy, dilated, with woolly hair and keratoderma | 605676 | Autosomal recessive | 3 | |
| Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis | 615821 | Autosomal dominant | 3 | |
| Epidermolysis bullosa, lethal acantholytic | 609638 | Autosomal recessive | 3 | |
| Keratosis palmoplantaris striata II | 612908 | Autosomal dominant | 3 |
Desmosomes are the most common type of intercellular junction in vertebrate epithelial cells. They are characterized by 2 forms of interaction with other cellular structures. First, they form membrane anchorage sites for intermediate-size filaments, which are seen as electron-dense plaques evident beneath the plasma membrane. Second, a specific membrane core domain interacts with a corresponding domain of the plasma membrane of an adjacent cell, apparently mediating intercellular adhesion in a stable way. The desmosome intermediate filament complex is thought to impart tensile strength and resilience to the epithelium. Desmosomal proteins can be divided into 2 groups based on whether they fractionate with the urea-insoluble 'core' or the urea-soluble 'plaque' components. Desmoglein (125670) is, for example, a protein of the core. The main proteins of the plaque comprise the desmoplakins and plakoglobin (173325).
DSPI and DSPII are related proteins of molecular mass 250 kD and 215 kD, respectively. They are splice variants of the same gene (Green et al., 1990).
Virata et al. (1992) identified overlapping cDNA clones predicted to encode a full-length 310-kD polypeptide of 2,677 amino acid residues. Stappenbeck et al. (1993) and Bornslaeger et al. (1996) made use of updated information on the desmoplakin protein sequence indicating that it contains 2,871 amino acids and has a molecular mass of approximately 332 kD.
By RT-PCR, Kazerounian et al. (2002) surveyed the tissue distribution of several plakin family members, including periplakin (602871), plectin (601282), desmoplakin, BPAG1 (113810), and envoplakin (601590). Desmoplakin was expressed at high levels in several tissues, but was only weakly expressed in adult brain and was not detected in skeletal muscle or leukocytes.
Whittock et al. (1999) determined that the desmoplakin gene spans approximately 45 kb of genomic DNA and consists of 24 exons ranging in size from 51 bp to 3,922 bp. RT-PCR of total RNA isolated from cultured skin keratinocytes followed by sequence analysis revealed a 700-bp 3-prime UTR containing a polyadenylation signal (AATAAA) and a poly(A) tail, indicating characterization of the entire 3-prime UTR.
By the study of somatic cell hybrids, Arnemann et al. (1991) mapped the DSP gene to chromosome 6pter-p21. Olavesen et al. (1997) reported fine mapping of 39 ESTs on 6p25-p23 that had previously been mapped in radiation hybrids. Most of the ESTs (31 of 39) were positioned in the 6p24-p23 interval; of these, 8 were located within a single PAC clone. DSP was the most telomeric of these 8 loci.
Anhalt et al. (1990) discovered an autoimmune disorder, which they called paraneoplastic pemphigus, associated with lymphoid malignancies, thymomas, and poorly differentiated sarcomas. Oursler et al. (1992) demonstrated that autoantibodies against the desmoplakins are an important component of the humoral autoimmune response in paraneoplastic pemphigus.
Keratosis Palmoplantaris Striata II
Armstrong et al. (1999) described the first heterozygous mutation in the DSP gene, in a family with a striate form of hereditary palmoplantar keratoderma, designated type II (PPKS2; 612908). The mutation was a C-to-T transition in exon 4, predicted to result in a premature termination codon in the N-terminal region of the peptide (125647.0001). Not only was this the first reported mutation of desmoplakin, but it was also said to be the first inherited skin disease in which haploinsufficiency of the structural element was implicated. Armstrong et al. (1999) concluded that dosage of desmoplakin is critical to the maintenance of epidermal integrity.
In a 45-year-old male construction worker with striate palmoplantar keratoderma, Whittock et al. (1999) identified heterozygosity for a splice site mutation in the DSP gene (125647.0024). His mildly affected mother and son, as well as his 3 unaffected sibs, were also heterozygous for the mutation. The authors concluded that trauma was clearly relevant to phenotypic expression in this family, since the clinical features were most prominent in the affected member who worked as a manual laborer, whereas his mother and sibs with sedentary jobs had mild or undetectable physical signs.
Dilated Cardiomyopathy with Woolly Hair and Keratoderma
Norgett et al. (2000) described the first recessive human mutation in the DSP gene, 7901delG (125647.0002), that causes a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair, and dilated left ventricular cardiomyopathy (Carvajal syndrome; 605676). A number of the patients with this syndromic disorder suffered heart failure in their teenage years, resulting in early morbidity. Histology of the skin revealed large intercellular spaces and clustering of desmosomes at the infrequent sites of keratinocyte adhesion. Immunohistochemistry of skin from the patients showed a perinuclear localization of keratin in suprabasal keratinocytes, suggesting a collapsed intermediate filament network.
In 2 unrelated girls with woolly hair, skin fragility, and PPK, Whittock et al. (2002) performed mutation screening of desmoplakin and identified compound heterozygosity for a missense/nonsense combination of mutations in both patients: N287K (125647.0004) and C809X (125647.0005) in proband A, and R2366C (125647.0006) and Q664X (125647.0007) in proband B. The unaffected parents in each family were heterozygous for 1 of the mutations. The authors noted that there were no apparent cardiac anomalies in the 2 probands, but stated that the patients would be at risk for dilated left ventricular cardiomyopathy.
In a 16-year-old Muslim Arab girl with woolly hair, an epidermolytic skin disorder, and arrhythmogenic right ventricular cardiomyopathy, Alcalai et al. (2003) identified homozygosity for a missense mutation in the DSP gene (G2375R; 125647.0025). The mutation segregated fully with disease in the family and was not found in 90 unrelated controls. DNA was unavailable from 8 additional family members with woolly hair and skin abnormalities who had died suddenly in young adulthood.
Uzumcu et al. (2006) described a patient with a recessively inherited arrhythmogenic dilated cardiomyopathy with left and right ventricular involvement, epidermolytic palmoplantar keratoderma, and woolly hair (605676). The patient showed a severe cardiac phenotype with an early onset and rapid progression to heart failure at 4 years of age. A homozygous nonsense mutation, R1267X, was found in exon 23 of the desmoplakin gene (125647.0010), which resulted in an isoform-specific truncation of the larger desmoplakin isoform I. The loss of most of the DSPI-specific rod domain and C-terminal area was confirmed by Western blotting and immunofluorescence. DSP isoform I had been reported to be an obligate constituent of desmosomes and the only isoform present in cardiac tissue. Uzumcu et al. (2006) confirmed that it is the major cardiac isoform, and also showed that several compartments of the heart have detectable expression of isoform II.
In a large consanguineous Saudi family in which 3 sibs and 2 cousins had woolly hair, skin fragility, and PPK mapping to chromosome 6p25.1-p24.1, Al-Owain et al. (2011) sequenced the candidate gene DSP and identified homozygosity for a missense mutation (R2366H; 125647.0013). None of the children had cardiac symptoms, and 2 had normal echocardiograms at ages 4 and 7 years; cardiac evaluation was declined for the remaining 3 children, aged 3, 14, and 16 years. Although the authors designated the patients as having skin fragility-woolly hair syndrome, they noted that cardiomyopathy sometimes occurs later in life in patients with DCWHK.
In a Turkish girl with Carvajal syndrome, Rasmussen et al. (2013) identified homozygosity for a 1-bp deletion in the DSP gene (125647.0014).
In a 4-year-old Swedish girl with alopecia, skin fragility, focal keratoderma, and dilated cardiomyopathy, Vahlquist et al. (2014) sequenced the DSP gene and identified compound heterozygosity for a 13-bp deletion (125647.0026) and a 1-bp deletion (125647.0027). Her unaffected parents were each heterozygous for 1 of the mutations.
Dilated Cardiomyopathy with Woolly Hair, Keratoderma, and Tooth Agenesis
In a female patient with dilated cardiomyopathy, palmoplantar keratoderma, woolly hair, and tooth agenesis (DCWHKTA; 615821), Norgett et al. (2006) identified heterozygosity for a 30-bp insertion in the DSP gene (125647.0015). The mutation was not present in her unaffected mother or 160 control chromosomes; no DNA was available from her deceased, similarly affected father.
In a father and son with DCWHKTA, Chalabreysse et al. (2011) identified heterozygosity for a missense mutation in the DSP gene (S597L; 125647.0016). A second affected son declined genetic testing.
In a father and son with DCWHKTA, Boule et al. (2012) analyzed the desmosomal genes DSP, JUP, PKP2 (602861), DSG2 (125671), and DSC2 (125645), and identified heterozygosity for a missense mutation in the DSP gene (T564I; 125647.0017). No mutations were detected in the other genes, and the DSP mutation was not found in 600 control chromosomes.
Boyden et al. (2016) analyzed exome data from a cohort of 496 kindreds with disorders of keratinization and identified 3 unrelated children with dilated cardiomyopathy, woolly hair, erythrokeratoderma, and tooth agenesis who were heterozygous for de novo tightly clustered missense mutations in the DSP gene: Q616P (125647.0021), H618P (125647.0022), and L622P (125647.0023).
Familial Arrhythmogenic Right Ventricular Dysplasia 8
In 1 of 16 families observed in northern Italy with arrhythmogenic right ventricular dysplasia mapped to chromosome 6p24 (ARVD8; 607450), Rampazzo et al. (2002) found that affected members were heterozygous for a missense mutation (S299R; 125647.0003) in exon 7 of the DSP gene. The authors noted that DSP, together with junction plakoglobin (JUP; 173325), anchors to desmosomal cadherins, forming an ordered array of nontransmembrane proteins, which then bind to keratin intermediate filaments. The S299R missense mutation is located in the N-terminal domain, which is involved in JUP binding and in clustering of desmosomal cadherin-JUP complexes. Rampazzo et al. (2002) considered it possible that the absence of skin defects in heterozygous carriers of the S299R mutation can be explained by considering that this mutation does not affect DSP-intermediate filament binding, which, on the contrary, is targeted by other mutations producing a keratoderma phenotype. In heterozygotes for the S299R mutation, most desmosomal cadherin-JUP complexes would be defective because of the dimeric nature of DSP functional molecules. This would explain the dominant pattern of inheritance in the disease caused by such a mutation.
In a mutation analysis of 66 probands with ARVD, Yang et al. (2006) identified 4 variants in DSP: V30M, Q90R, W233X, and R2834H (125647.0012). To establish a cause and effect relationship between these DSP missense mutations and ARVD, they performed in vitro and in vivo analyses of the mutant proteins. Unlike wildtype DSP, the N-terminal mutants (V30M and Q90R) failed to localize to the cell membrane in a desmosome-forming cell line and failed to bind to and coimmunoprecipitate junction plakoglobin. Multiple attempts to generate N-terminal DSP (V30M and Q90R) cardiac-specific transgenes failed; analysis of embryos revealed evidence of profound ventricular dilation, which likely resulted in embryonic lethality. Yang et al. (2006) were able to develop transgenic (Tg) mice with cardiac-restricted overexpression of the C-terminal mutant (R2834H) or wildtype DSP. Whereas mice overexpressing wildtype DSP had no detectable histologic, morphologic, or functional cardiac changes, the R2834H-Tg mice had increased cardiomyocyte apoptosis, cardiac fibrosis, and lipid accumulation, along with ventricular enlargement and cardiac dysfunction in both ventricles. These mice also displayed interruption of DSP-desmin interaction at intercalated discs and marked ultrastructural changes of these discs. The data suggested that DSP expression in cardiomyocytes is crucial for maintaining cardiac tissue integrity, and that DSP abnormalities result in ARVD by cardiomyocyte death, changes in lipid metabolism, and defects in cardiac development. The pathogenicity of the V30M mutation was later called into question (see 125647.0011).
Rasmussen et al. (2013) studied 4 patients with mutations in the DSP gene, 3 ARVD patients and 1 patient with Carvajal syndrome. The mutation carriers had abnormal DSP expression in both myocardial and epidermal tissue; disease mechanisms included haploinsufficiency, dominant-negative effects, or both. The authors concluded that because protein abnormalities in cardiac tissue from patients with desmosomal cardiomyopathies are also present in their keratinocytes, human keratinocyte cultures from affected individuals can be used for protein expression studies and elucidation of molecular disease mechanisms.
In a cohort of 65 patients with ARVD, Christensen et al. (2010) screened 5 desmosomal genes as well as the TGFB3 gene (190230) and identified 1 patient who was heterozygous for the c.939+1G-A splice site mutation in the DSP gene (125647.0024), which had previously been identified in a family with striate palmoplantar keratoderma. Skin and hair findings were not reported in the ARVD patient.
Lethal Acantholytic Epidermolysis Bullosa
Jonkman et al. (2005) reported a patient with severe fragility of skin and mucous membranes caused by genetic truncation of the desmoplakin tail. They named the disorder, from which the infant died at the age of 10 days, 'lethal acantholytic epidermolysis bullosa' (EBLA; 609638). Skin fragility was accompanied by universal alopecia, neonatal teeth, and nail loss. The patient died from immense transcutaneous fluid loss. Histology showed suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Electron microscopy showed disconnection of keratin intermediate filaments from desmosomes. Immunofluorescence staining of desmoplakin showed a distinct punctate intercellular pattern in the patient's skin. Protein analysis showed expression of truncated desmoplakin polypeptides. Mutation analysis showed that the patient was a compound heterozygote for 2 DSP mutations, R1934X (125647.0008) and 6370delTT (125647.0009). Aberrant mRNA transcripts that predicted premature termination of translation with a loss of the 3 intermediate filament-binding subdomains in the DP tail were detected by RT-PCR.
In 2 brothers with lethal acantholytic epidermolysis bullosa (LAEB/EBLA) from a consanguineous Yemeni family, Bolling et al. (2010) identified homozygosity for a 5-bp deletion in the DSP gene (125647.0018), resulting in truncation of the C terminus and entire rod domain. Electron microscopy of affected skin showed lack of the desmosomal inner dense plaque, in contrast to the previously reported patient (Jonkman et al., 2005), whose mutations truncated only the desmoplakin C terminus and in whom normal desmosomes were seen. Bolling et al. (2010) concluded that the desmoplakin rod comprises the inner dense plaque.
In an infant girl with EBLA, Hobbs et al. (2010) identified homozygosity for a 1-bp deletion in the DSP gene (125647.0019).
Associations Pending Confirmation
For discussion of a possible association between variation in the DSP gene and congenital erythroderma with palmoplantar keratoderma, hypotrichosis, and hyper-IgE, see 125647.0020.
Vasioukhin et al. (2001) generated a desmoplakin mouse knockout and showed that epidermal integrity requires desmoplakin. Mechanical stresses to DP-null skin cause intercellular separations. The number of epidermal desmosomes in DP-null skin was similar to wildtype, but they lacked keratin filaments, which compromise their function. DP-null keratinocytes have few desmosomes in vitro, and are unable to undergo actin reorganization and membrane sealing during epithelial sheet formation. Adherens junctions were also reduced. In vitro, DP transgene expression rescued these defects. Desmoplakin is therefore required for assembly of functional desmosomes, maintaining cytoskeletal architecture, and reinforcing membrane attachments essential for stable intercellular adhesion.
In a large kindred with a striate subtype of palmoplantar keratoderma and demonstrated linkage of the disorder to 6p21 (PPKS2; 612908), Armstrong et al. (1999) identified a heterozygous C-to-T transition at nucleotide 1323 (c.1323C-T) in exon 4, converting a glutamine residue to a stop codon (gln331 to ter). The mutation was not detected on cDNA screening. The absence of RNA transcribed from the mutant allele in keratinocytes suggested that nonsense-mediated mRNA decay was operative in this kindred, resulting in a functionally null allele and desmoplakin haploinsufficiency.
Norgett et al. (2000) described the first recessive human mutation in the DSP gene, c.7901delG, which causes a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair, and a dilated left ventricular cardiomyopathy (DCWHK; 605676). The mutation was predicted to cause a premature stop codon to be inserted 18 codons downstream from the deletion and to result in the truncation of the C domain in the tail region of the protein. This region of the desmoplakin protein interacts with intermediate filaments to anchor them to the desmosome (Bornslaeger et al., 1996). All tested affected members of 3 families from Ecuador were homozygous for the mutation. While desmoplakin-null mice die early in development, the human c.7901delG mutation is not embryonic lethal. The authors hypothesized that the tail domain of desmoplakin is not required for establishing tissue architecture during development.
In affected members of an Italian family with arrhythmogenic right ventricular dysplasia mapping to 6p24 (ARVD8; 607450), Rampazzo et al. (2002) identified a heterozygous missense mutation, ser299-to-arg (S299R), in exon 7 of the DSP gene.
In a 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: an c.861G-T transversion in exon 7, resulting in an asn287-to-lys (N287K) substitution, and a c.2427T-A transversion in exon 17, resulting in a cys809-to-ter (C809X; 125647.0005) substitution. The C809X allele resulted in nonsense-mediated mRNA decay and only the N287K DSP gene product was expressed, resulting in a severe keratoderma phenotype. Although the patient had no apparent cardiac anomalies, the authors considered her to be at risk for dilated left ventricular cardiomyopathy.
For discussion of the cys809-to-ter (C809X) mutation in the DSP gene that was found in compound heterozygous state in a patient with woolly hair, skin fragility, and disabling palmoplantar keratoderma (DCWHK; 605676) by Whittock et al. (2002), see 125647.0004.
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.
For discussion of the gln664-to-ter (Q664X) mutation in the DSP gene that was found in compound heterozygous state in a 17-year-old girl with woolly hair, skin fragility, and disabling palmoplantar keratoderma (DCWHK; 605676) by Whittock et al. (2002), see 125647.0006.
In an infant with lethal acantholytic epidermolysis bullosa (EBLA; 609638), Jonkman et al. (2005) found compound heterozygosity for 2 mutations in exon 24 of the DSP gene. A c.6079C-T transition, resulting in an arg1934-to-ter (R1934X) substitution, was inherited from the father, and a 2-bp deletion (6370delTT; 125647.0009), predicting a frameshift resulting in a novel sequence beginning at amino acid 2031 and a premature termination at position 2058, was inherited from the mother. The heterozygous parents were nonconsanguineous and phenotypically normal.
For discussion of the 2-bp deletion in the DSP gene (c.6370delTT) that was found in compound heterozygous state in an infant with lethal acantholytic epidermolysis bullosa (EBLA; 609638) by Jonkman et al. (2005), see 125647.0008.
In the child of consanguineous Turkish parents with recessively inherited arrhythmogenic dilated cardiopathy with left and right ventricular involvement, epidermolytic palmoplantar keratoderma, and woolly hair (DCWHK; 605676), Uzumcu et al. (2006) found a homozygous nonsense mutation, arg1267 to stop (R1267X), in exon 23 of the desmoplakin gene, which resulted in an isoform-specific truncation of the larger isoform I of desmoplakin. The amino acid substitution arose from a c.3799C-T transition. The loss of most of the DSPI-specific rod domain and C-terminal area was confirmed by Western blotting and immunofluorescence.
This variant, formerly titled ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8, has been reclassified because its contribution to the phenotype has not been confirmed.
In a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD8; 607450), Yang et al. (2006) identified an c.88G-A transition in the DSP gene, resulting in a val30-to-met (V30M) substitution.
Hamosh (2016) noted that the c.88G-A mutation (rs121912998) was identified in 149 of 47,946 alleles in the ExAC browser (January 6, 2016). One individual was homozygous for the variant.
In a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD8; 607450), Yang et al. (2006) identified an c.8501G-A transition in the DSP gene, resulting in an arg2834-to-his (R2834H) substitution.
In a large consanguineous Saudi family in which 3 sibs and 2 cousins had woolly hair, skin fragility, and palmoplantar keratoderma (DCWHK; 605676), Al-Owain et al. (2011) identified homozygosity for a c.7097G-A transition in the DSP gene, resulting in an arg2366-to-his (R2366H) substitution. The parents in both sibships were heterozygous for the mutation, which was not found in 400 chromosomes from healthy control individuals of the same ethnic group. No cardiac symptoms were reported and there was no family history of sudden death. A normal echocardiographic evaluation was found in 2 of those affected who were 4 and 7 years of age; formal cardiac workup was refused in the other 3 affected members, aged 3, 14, and 16 years. Although the authors designated the patients as having skin fragility-woolly hair syndrome, they noted that that diagnosis was not beyond doubt, since cardiomyopathy sometimes occurs later in life in patients with DCWHK.
In a Turkish girl with woolly hair and palmoplantar keratoderma who had congestive heart failure requiring cardiac transplantation at age 12 years, consistent with a diagnosis of Carvajal syndrome (DCWHK; 605676), Rasmussen et al. (2013) identified homozygosity for a 1-bp deletion (c.7780delT) in the last exon of the DSP gene, causing a frameshift predicted to result in a premature termination codon (Ser2594PhefsTer8). Her unaffected first-cousin parents and 2 sibs were heterozygous for the deletion. Expression studies in cultured keratinocytes and immunohistochemistry of epidermal and myocardial tissue in the proband and her mother indicated that the homozygous patient incorporated mutant DSP into myocardial and epidermal desmosomes, whereas the mutant DSP was almost entirely degraded in the healthy heterozygous mother, in whom expression of wildtype DSP was reduced by 50% compared to controls.
In a girl with dilated cardiomyopathy, keratoderma, woolly hair, and tooth agenesis (DCWHKTA; 615821) who died at age 18 years, Norgett et al. (2006) identified heterozygosity for a 30-bp insertion between the second and third nucleotides of codon 608 in exon 14 of the DSP gene, causing a frameshift and addition of 10 amino acids (QSQFTDARKI) in the N terminus. The mutation was not present in the girl's unaffected mother or in 160 control chromosomes; no DNA was available from her deceased, similarly affected father. Immunofluorescence analysis of desmoplakin and junction plakoglobin (JUP; 173325) in a skin biopsy from the proband showed that unlike control specimens, the distribution of these proteins was not continuous around the cell membrane and there was some cytoplasmic localization; in contrast, localization of keratin-1 (KRT1; 139350) in patient skin was comparable to that in normal skin.
In a father and son with dilated cardiomyopathy, palmoplantar keratoderma, woolly hair, and tooth agenesis (DCWHKTA; 615821), Chalabreysse et al. (2011) identified heterozygosity for a c.1790C-T transition in exon 14 of the DSP gene, resulting in a ser597-to-leu (S597L) substitution at a highly conserved residue in the plakin domain. The proband's affected older brother declined genetic testing. The mutation was not found in the unaffected mother, paternal grandparents, 2 unaffected sibs, or in 100 control chromosomes.
In a father and son with dilated cardiomyopathy, palmoplantar keratoderma, woolly hair, and tooth agenesis (DCWHKTA; 615821), Boule et al. (2012) identified heterozygosity for a c.1691C-T transition in the DSP gene, resulting in a thr564-to-ile (T564I) substitution at a highly conserved residue. The mutation was not found in 600 control chromosomes.
In 2 brothers from a consanguineous Yemeni family who died within the first few days of life from lethal acantholytic epidermolysis bullosa (EBLA; 609638), Bolling et al. (2010) identified homozygosity for a 5-bp deletion in the exon-intron boundary of intron 20 of the DSP gene (c.2874del5), comprising the four 3-prime-most nucleotides of exon 20 and the first nucleotide of intron 20. The mutation, which disrupts the donor splice site, was predicted to result in a premature termination codon (Lys959MetfsTer5), with truncation of the C terminus and entire rod domain. The mutation was not found in 100 control DNA samples. The authors gave the location of the mutation according to the genomic sequence as 35403del5 (GRCh38) and the mRNA location as 3153del5.
In an infant girl who died at 26 days of life from lethal acantholytic epidermolysis bullosa (EBLA; 609638), Hobbs et al. (2010) identified homozygosity for a 1-bp deletion (c.7248delT) in exon 24 of the DSP gene, causing a frameshift predicted to result in premature termination (Phe2416LeufsTer14) within the plakin-repeat domain B. The patient's unaffected consanguineous parents were each heterozygous for the deletion. Patient keratinocytes exhibited reduced E-cadherin (192090) and elevated N-cadherin (114020) levels compared to controls, and fibronectin (135600) was elevated in cell lysates. In addition, plakoglobin (173325) and, to a lesser extent, beta-catenin (116806) were observed in nuclei of patient keratinocytes. Hobbs et al. (2010) proposed that elevated N-cadherin and fibronectin might facilitate reepithelialization in patient skin, and that loss of desmoplakin might trigger a 'cadherin switch.'
This variant is classified as a variant of unknown significance because its contribution to a syndrome involving congenital erythroderma associated with palmoplantar keratoderma, hypotrichosis, and hyper-IgE (see EPKHE, 615508) has not been confirmed.
McAleer et al. (2015) studied an Irish boy with congenital erythroderma, ichthyosis, palmoplantar keratoderma, nail dystrophy, diffuse hypotrichosis with woolly hair, marked hypodontia, and mild global developmental delay. He was also atopic with multiple food allergies and showed persistent eosinophilia and increased IgE levels. Cardiac evaluation, including echocardiography, was unremarkable. Initial screening of the proband's DNA was negative for mutation in SPINK5 (605010) and ADAM17 (603639) as well as for 8 ichthyosis-associated genes and 2 pustular psoriasis-associated genes. Whole-exome sequencing revealed no pathogenic variants in the EPKHE-associated gene DSG1 (125670), but identified a de novo heterozygous c.1757A-C transversion in the DSP gene, resulting in a his586-to-pro (H586P) substitution in the conserved alpha-helix within spectrin repeat 6. No copy number changes were detected in DSP or in DSG1 using high-density aCGH. The mutation was not found in his parents or in 100 ethnically matched controls. Immunofluorescence analysis revealed aberrant desmoplakin staining, appearing as large aggregates; in addition, striking reductions in both DSG1 and keratin-10 (148080) staining were observed, and DSG1 appeared in aggregates.
In a boy who died at 3 years of age from heart failure due to dilated cardiomyopathy, who also exhibited woolly hair, erythrokeratodermia, and tooth agenesis (DCWHKTA; 615821), Boyden et al. (2016) identified heterozygosity for a de novo A-to-C transversion (chr6:7,571,761, GRCh37) in exon 14 of the DSP gene, resulting in a gln616-to-pro (Q616P) substitution at a highly conserved residue within spectrin repeat 6. The mutation was not present in the proband's parents, in approximately 2,500 control exomes, or in public variant databases, including the ExAC Browser. Immunolocalization analysis demonstrated an overall reduction in signal intensity and more diffuse localization with the Q616P mutant than with wildtype DSP. In addition, DSG1 (125670) staining was less tightly localized to intercellular junctions in patient skin than control, and JUP (173325) staining remained cytoplasmic and diffuse in basal cells, with weaker and more diffuse intercellular localization in suprabasal cells, compared to normal skin. GJA1 (121014) expression in patient skin showed diminished membrane-staining intensity and a more diffuse intercellular localization compared to control. Electron microscopy of patient skin showed a reduced number of desmosomes in suprabasal layers, likely due to marked aggregation of desmosomes through shedding or internalization in spinous layer keratinocytes. Widening of intercellular spaces in suprabasal cells due to loss of desmosomes was observed. Ruthenium tetroxide staining revealed marked deficits in lipid processing and secretion, with premature secretion of lamellar bodies which had defective structure and supramolecular organization.
In an 8-year-old boy with dilated cardiomyopathy, woolly hair, erythrokeratodermia, and tooth agenesis (DCWHKTA; 615821), Boyden et al. (2016) identified heterozygosity for a de novo A-to-C transversion (chr6:7,571,767, GRCh37) in exon 14 of the DSP gene, resulting in a his618-to-pro (H618P) substitution at a highly conserved residue within spectrin repeat 6. The mutation was not present in the proband's parents, in approximately 2,500 control exomes, or in public variant databases, including the ExAC Browser. Expression analysis in primary human keratinocytes demonstrated a reduction in GJA1 (121014) membrane intensity with the H618P mutant to less than 80% compared to wildtype DSP. In addition to his ectodermal features, the proband also had photophobia and corneal opacities with severe visual impairment, and exhibited developmental delay with verbal expression limited to simple sentences.
In a girl with dilated cardiomyopathy, woolly hair, erythrokeratodermia, and tooth agenesis (DCWHKTA; 615821), Boyden et al. (2016) identified heterozygosity for a de novo T-to-C transition (chr6:7,571,779, GRCh37) in exon 14 of the DSP gene, resulting in a leu622-to-pro (L622P) substitution at a highly conserved residue within spectrin repeat 6. The mutation was not present in the proband's parents, in approximately 2,500 control exomes, or in public variant databases, including the ExAC Browser. Expression analysis in primary human keratinocytes demonstrated a reduction in GJA1 (121014) membrane intensity with the L622P mutant to less than 80% compared to wildtype DSP.
Keratosis Palmoplantaris Striata II
In a 45-year-old male construction worker with striate palmoplantar keratoderma (PPKS2; 612908), Whittock et al. (1999) identified heterozygosity for a splice site mutation (939+1G-A) in intron 7 of the DSP gene. Nested PCR of patient cDNA revealed that all 856 bp of intron 7 were included in the mRNA, causing a termination codon 25 amino acids downstream. The proband's mildly affected mother and son and his 3 unaffected sibs were also heterozygous for the mutation, which was not found in 100 ethnically matched control chromosomes. The authors concluded that trauma was clearly relevant to phenotypic expression in this family, since the clinical features were most prominent in the affected member who worked as a manual laborer, whereas his mother and sibs with sedentary jobs had mild or undetectable physical signs.
Arrhythmogenic Right Ventricular Dysplasia, Familial, 8
In a patient with arrhythmogenic right ventricular dysplasia (ARVD8; 607450), Christensen et al. (2010) identified heterozygosity for the c.939+1G-A splice site mutation (c.939+1G-A, NM_004415) in the DSP gene. Skin findings were not reported for this patient.
In a 16-year-old Muslim Arab girl with woolly hair, an epidermolytic skin disorder, and arrhythmogenic right ventricular cardiomyopathy with dilation of the right ventricle (DCWHK; 605676), Alcalai et al. (2003) identified homozygosity for a c.7402G-C transversion in exon 24 of the DSP gene, resulting in a gly2375-to-arg (G2375R) substitution at a highly conserved residue. The mutation segregated fully with disease in the family and was not found in 90 unrelated controls. DNA was unavailable from 8 additional family members with skin and hair abnormalities who had died suddenly in young adulthood, at ages ranging from 15 to 30 years; none had major cardiac symptoms before death and none underwent cardiac evaluation.
In transiently transfected HEK293T cells, Favre et al. (2018) observed that, in contrast to wildtype DSP, the G2375R mutant (c.7123G-C, NM_004415) did not bind strongly to cytokeratins or the type III intermediate filament proteins vimentin or muscle-specific desmin. In transfected Dsp -/- mouse keratinocytes, wildtype DSP colocalized with the K5 (KRT5; 148040)/K14 (KRT14; 148066) network or displayed a dotted pattern along it, whereas the G2375R mutant showed a diffuse cytosolic distribution. In transfected HaCaT keratinocytes, the wildtype DSP tail coaligned with the K5/K14 network more frequently than the mutant tail, and the latter was typically concentrated around the nucleus and showed no obvious filamentous network pattern in the cytoplasm. In transfected SW13 cells, the G2375R mutant tail also coaligned with the vimentin network less frequently than the wildtype DSP tail; the same phenomenon was observed with the rudimentary desmin network in SW13 vimentin-negative cells coexpressing desmin.
In a 4-year-old Swedish girl with dilated cardiomyopathy, sparse hair, skin fragility, and keratoderma (DCWHK; 605676), Vahlquist et al. (2014) identified compound heterozygosity for deletions in the DSP gene: a 13-bp deletion in exon 23 (c.4778_4790del13), and a 1-bp deletion in exon 24 (c.6310delA), both causing frameshifts predicted to result in premature termination codons (Lys1593SerfsTer5, and Thr2104GlnfsTer12, respectively). Her unaffected parents were each heterozygous for 1 of the deletions. Immunohistochemistry demonstrated that there was Virtually no expression of desmoplakin in the proband's epidermis.
For discussion of the 1-bp deletion (c.6310delA) in exon 24 of the DSP gene, causing a frameshift predicted to result in a premature termination codon (Thr2104GlnfsTer12), that was found in compound heterozygous state in a 4-year-old Swedish girl with dilated cardiomyopathy, sparse hair, skin fragility, and keratoderma (DCWHK; 605676) by Vahlquist et al. (2014), see 125647.0026.
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