In order to elucidate the genetic cause of PPKP type Buschke-Fischer-Brauer (PPKP1), we performed exome sequencing in five affected individuals from three families, and we identified in chromosomal region 15q22.33-q23 two heterozygous nonsense mutations-c.370C>T (p.Arg124(∗)) and c.481C>T (p.Arg161(∗))-in AAGAB in all affected individuals.
In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin-binding protein p34, located at a previously linked locus at 15q22.
Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by transgrediens PPK, associated with mutations in the secreted LY6/PLAUR domain containing 1 (SLURP1) gene.
The hypomorphic Egfr allele, which leads to reduced EGFR signalling in keratinocytes, did not ameliorate the PPK elicited by SLURP1 deficiency, suggesting that SLURP1 deficiency causes PPK independently (or downstream) from the EGFR pathway.
We performed mutational analysis by direct sequencing of SLURP-1 gene in order to identify the genetic defect in three unrelated families (families MDM-12, MDM-13, and MDM-14) variably affected with transgressive palmoplantar keratoderma.
Our cases for comparison included 4 cases with Mal de Meleda PPK associated with autosomal-recessive SLURP1 mutations, one case with pachyonychia congenita type II PPK associated with an autosomal-dominant KRT17 mutation, and one case with focal PPK associated with an autosomal-dominant KRT16 mutation.
Mutations in the SLURP1 gene are the cause of Mal de Meleda (MDM), a rare autosomal recessive genetic disease, characterized by inflammatory palmoplantar keratoderma.
We report here a Tunisian family with three siblings presenting with recessive transgressive PPK closely resembling the MDM phenotype that excludes linkage to the ARS gene.
Mal de Meleda is a recessive, transgressive palmoplantar keratoderma for which we previously identified mutations in the gene encoding secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1).
The p.Lys22AsnGJB2 mutation causes a dominant form of hearing loss associated with variable expression of palmoplantar keratoderma, representing a model of full penetrance, with an age-dependent effect on the phenotype.
These findings suggest a common mechanism whereby Cx26 mutations causing PPK and deafness transdominantly influence multiple functions of wild-type Cx43.
When the disease is associated with a mutation in cytokeratin 1, it may be related to hyperkeratosis of palms and soles, but this is not usually found when cytokeratin 10 is mutated.
Our findings provide further evidence of a correlation between the p.R75Q mutation in Cx26 and a syndromic hearing impairment with palmoplantar keratoderma.