225 Defects in Immune Regulatory Genes in a Family with Familial Pityriasis Rubra Pilaris – Novel Hints for Disease Mechanism

The purpose of our study was to detect the causative mutation in a family with familial pityriasis rubra pilaris (fPRP). We furthermore aimed to reveal the cause of an incomplete penetrance of a pathogenic CARD14 mutation in this family in order to detect novel genes involved in the mechanism of fPRP. We performed Sanger sequencing of CARD14, whole exome sequencing (WES) and RNA-expression arrays of gDNA or RNA from blood of five family members. The index patient, her parents, and her two half brothers were investigated by a dermatologist. Four unrelated healthy individuals were included in the RNA array as controls. Results of WES and RNA array were verified by Sanger sequencing or real-time qPCR, respectively. Sanger sequencing showed all family members, except the skin-wise healthy mother, to carry a pathogenic heterozygous CARD14 mutation c.371T>C (NM024110). Three mutation carriers were affected by PRP. One mutation carrier instead, was affected by psoriasis vulgaris, which to our knowledge is the first reported individual with psoriasis carrying a mutation causative for fPRP. WES revealed several psoriasis-associated mutations. However, none of these segregated with psoriasis or PRP. Furthermore, we detected heterozygous frameshift mutations in two immune regulatory genes. These rare variants segregated with PRP or were present in the psoriasis-affected individual only. According to the known functional protein domains, both mutations are expected to decrease protein function. One mutation, present in the individual with psoriasis only, affects a known regulator of transcription. As a consequence, we could show low mRNA-levels of regulated transcripts compared to fPRP-affected relatives and healthy control individuals. Our study reveals two possible modifiers of fPRP and indicates a role for regulatory T-cells and antigen presentation via MHCI in the disease mechanism.