Mutations in the desmoglein 1 gene in five Pakistani families with striate palmoplantar keratoderma

Dua-Awereh, Martha; Shimomura, Yutaka; Kraemer, Liv; Wajid, Muhammad; Christiano, Angela M.

doi:10.1016/j.jdermsci.2008.11.005

Cited by 23 publications

(12 citation statements)

References 19 publications

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“…pemphigus foliaceus, staphylococcal scaled skin syndrome and genetic disorders . Desmoglein 1 haploinsufficiency has been known for many years to cause autosomal dominant striate palmoplantar keratoderma . In the mother of our patient, the heterozygous mutation p.R887* led only to minor focal keratoses of the soles.…”

Section: Discussionmentioning

confidence: 67%

Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies

Has

Jakob

et al. 2014

Br J Dermatol

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Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss-of-function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.

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Section: Discussionmentioning

confidence: 67%

Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies

Has

Jakob

et al. 2014

Br J Dermatol

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“…In family 2, the proband had focal palmoplantar disease, and it was only when another relative presented with striate palmar disease that DSG1 screening was performed, which highlights the importance of examining multiple family members. The recurrent mutation in families 2 and 3 (c.76C>T) has been reported in three other pedigrees – sporadic striate PPK, diffuse nonepidermolytic PPK, and striate palmar and focal plantar keratoderma . DSG1 screening has hitherto been performed primarily for striate PPK.…”

Section: Discussionmentioning

confidence: 99%

Mutations in desmoglein 1 cause diverse inherited palmoplantar keratoderma phenotypes: implications for genetic screening

et al. 2017

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SummaryThe inherited palmoplantar keratodermas (PPKs) are a heterogeneous group of genodermatoses, characterized by thickening of the epidermis of the palms and soles. No classification system satisfactorily unites clinical presentation, pathology and molecular pathogenesis. There are four patterns of hyperkeratosis – striate, focal, diffuse and punctate. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate, but also in focal and diffuse PPKs. We report seven unrelated pedigrees with dominantly inherited PPK owing to mutations in the DSG1 gene, with marked phenotypic variation. Genomic DNA from each family was isolated, and individual exons amplified by polymerase chain reaction. Sanger sequencing was employed to identify mutations. Mutation analysis identified novel mutations in five families (p.Tyr126Hisfs*2, p.Ser521Tyrfs*2, p.Trp3*, p.Asp591Phefs*9 and p.Met249Ilefs*6) with striate palmar involvement and varying focal or diffuse plantar disease, and the recurrent mutation c.76C>T, p.Arg26*, in two families with variable PPK patterns. We report one recurrent and five novel DSG1 mutations, causing varying patterns of PPK, highlighting the clinical heterogeneity arising from mutations in this gene.

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“…A subset of patients with striate palmoplantar keratoderma (SPPK) are DSG1 deficient, with keratinization defects resembling, to an extent, cutaneous symptoms associated with RASopathies (2,6,7,(15)(16)(17)(18). That these genetic disorders often arise from mutations in ancillary regulators of MAPK signaling highlights the importance of identifying proteins that provide the physical link between DSG1 cytoplasmic domains and the core MAPK machinery.…”

Section: Introductionmentioning

confidence: 99%

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

Harmon

Simpson²,

Johnson³

et al. 2013

J. Clin. Invest.

131

158

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Genetic disorders of the Ras/MAPK pathway, termed RASopathies, produce numerous abnormalities, including cutaneous keratodermas. The desmosomal cadherin, desmoglein-1 (DSG1), promotes keratinocyte differentiation by attenuating MAPK/ERK signaling and is linked to striate palmoplantar keratoderma (SPPK). This raises the possibility that cutaneous defects associated with SPPK and RASopathies share certain molecular faults. To identify intermediates responsible for executing the inhibition of ERK by DSG1, we conducted a yeast 2-hybrid screen. The screen revealed that Erbin (also known as ERBB2IP), a known ERK regulator, binds DSG1. Erbin silencing disrupted keratinocyte differentiation in culture, mimicking aspects of DSG1 deficiency. Furthermore, ERK inhibition and the induction of differentiation markers by DSG1 required both Erbin and DSG1 domains that participate in binding Erbin. Erbin blocks ERK signaling by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2, a protein genetically linked to the RASopathy, Noonan-like syndrome with loose anagen hair (NS/LAH). DSG1 overexpression enhanced this inhibitory function, increasing Erbin-SHOC2 interactions and decreasing Ras-SHOC2 interactions. Conversely, analysis of epidermis from DSG1-deficient patients with SPPK demonstrated increased Ras-SHOC2 colocalization and decreased Erbin-SHOC2 colocalization, offering a possible explanation for the observed epidermal defects. These findings suggest a mechanism by which DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation.

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Mutations in the desmoglein 1 gene in five Pakistani families with striate palmoplantar keratoderma

Cited by 23 publications

References 19 publications

Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies

Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies

Mutations in desmoglein 1 cause diverse inherited palmoplantar keratoderma phenotypes: implications for genetic screening

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

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