Inherited MST1 deficiency underlies susceptibility to EV-HPV infections

Abstract

Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare ERCC3 variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.

Figure 1. Homozygous MST1 nonsense mutation in one patient with EV-HPV, bacterial and fungal infections.

(A) Pedigree of the family with EV-HPV, bacterial and fungal infections. Generations are designated by a Roman numeral (I, II). P1 is represented by a black symbol. The symbol *indicates the individuals genotyped with the Affymetrix Genome-wide SNP 6.0 array. The Familial segregation of the mutation R115X is shown on the pedigree. (B) Automated sequencing profile, showing the R115X MST1 mutation in gDNA extracted from EBV-B cells from the patient and comparison with the sequence obtained from a healthy control. The C→T mutation leads to the replacement at residue 115 of an Arg (R) residue by a STOP codon (X). (C) Schematic representation of the structure of the MST1 protein adapted from the work of Nehme et al. . R115X is situated in the kinase domain, close to the previously reported R117X mutation described by Nehme et al., indicated by a black arrow. The second mutation (1103delT X369) described by Nehme et al., 1103delT X369, and the mutation described by Abdollahpour et al. (W250X) are also indicated by black arrows.