SLURP1 – mal de Meleda

SLURP1 mutations are causative for mal de Meleda, a rare autosomal recessive palmoplantar keratoderma characterized by transgrediens hyperkeratosis and variable extracutaneous features. Multiple independent studies have identified biallelic SLURP1 mutations in affected individuals, supporting a robust gene‑disease association (PMID:14674887).

Clinical data from case reports and family studies consistently show that patients harboring homozygous or compound heterozygous mutations in SLURP1 often exhibit the classical dermatologic phenotype with additional findings such as brachydactyly, sclerodactyly, and amniotic constriction rings (PMID:29226984). Such segregation of pathogenic variants in consanguineous families further strengthens the clinical validity of the association (PMID:11285253).

Genetic evidence is compelling with multiple distinct pathogenic variants reported. For example, the recurrent pathogenic variant c.256G>A (p.Gly86Arg) has been identified in several unrelated probands and serves as a representative change that fulfills stringent HGVS criteria and is supported by independent studies (PMID:35360724).

Segregation analyses in extended pedigrees have revealed that additional affected relatives consistently carry the same biallelic SLURP1 mutations, reinforcing the autosomal recessive mode of inheritance. These findings have been validated by linkage studies in several large consanguineous families (PMID:11285253).

Functional studies complement the genetic data by demonstrating that SLURP1 mutations disrupt protein function. In vitro assessments have shown impaired T‑cell activation and abnormal keratinocyte signaling, consistent with defects in epidermal homeostasis. Computational predictions and in silico modeling further corroborate the loss‑of‑function effect of these mutations (PMID:20854438, PMID:31882421).

The integration of genetic, segregation, and experimental evidence provides a coherent narrative that underscores the utility of SLURP1 mutational analysis in the diagnostic workup of mal de Meleda. Notably, the convergence of these data supports the clinical use of SLURP1 testing for early diagnosis and tailored management.

Key take‑home sentence: The strong genetic and functional evidence for SLURP1 mutations in mal de Meleda supports the incorporation of molecular testing into clinical diagnostic pathways.

References

• The British journal of dermatology • 2011 • SLURP1 mutation‑impaired T‑cell activation in a family with mal de Meleda PMID:20854438
• Clinical and experimental dermatology • 2016 • A novel homozygous mutation disrupting the initiation codon in the SLURP1 gene underlies mal de Meleda in a consanguineous family PMID:29226984
• Human molecular genetics • 2001 • Mutations in the gene encoding SLURP‑1 in Mal de Meleda PMID:11285253
• Annals of clinical and laboratory science • 2019 • In-silico Analyses of Disease Causing Mutations in SLURP1 Gene PMID:31882421

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