DSG1 and striate palmoplantar keratoderma

The association between DSG1 and striate palmoplantar keratoderma has been documented over the past decades, with multiple independent studies demonstrating an autosomal dominant inheritance pattern. Early evidence identified an alteration in splicing that results in the deletion of a critical extracellular domain of DSG1, leading to marked hyperkeratotic bands on the palms and soles (PMID:10332028).

Subsequent case reports and multi‐patient studies have confirmed the genetic association by identifying pathogenic variants in diverse families. In one series, nine affected individuals from three families were found to harbor heterozygous mutations in DSG1, supporting robust segregation of the variant with disease (PMID:19018793).

Genetic evidence is further reinforced by the identification of multiple variant classes, including splice site and frameshift mutations. For instance, the frameshift variant c.1771_1784del (p.Asp591fs) has been reported in affected individuals and is consistent with a loss‐of‐function mechanism that leads to a compromised desmosomal adhesion function.

Functional studies support these genetic findings by demonstrating that mutated DSG1 results in defects in desmosome assembly and adhesion. Experimental models have shown reduced DSG1 expression and impaired cell–cell adhesion, which correlate with the clinical presentation of striate palmoplantar keratoderma (PMID:34352264).

In-depth analyses reveal that the pathogenic mechanism likely involves haploinsufficiency, where decreased DSG1 levels impede proper desmosomal integrity in the epidermis. Additional studies have noted that even subtle alterations in DSG1 structure can disrupt lipid raft targeting, further compromising desmosome function.

Key take‐home: The integration of robust genetic evidence with mechanistic functional studies convinces that DSG1 variants, such as c.1771_1784del (p.Asp591fs), reliably contribute to the autosomal dominant striate palmoplantar keratoderma phenotype, supporting its use in diagnostic decision‑making and clinical management.

References

• Human molecular genetics • 1999 • N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma PMID:10332028
• Clinical and experimental dermatology • 2009 • Novel mutations in DSG1 causing striate palmoplantar keratoderma PMID:19018793
• The Journal of investigative dermatology • 2022 • Differential pathomechanisms of desmoglein 1 transmembrane domain mutations in skin disease PMID:34352264

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