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.

Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency

“…Infection by EV-specific b-HPV genotypes has also been demonstrated in 2 autosomal recessive disorders affecting T-cell immunity; RHOH deficiency, 32 and MST1 deficiency. 33 TPP2 deficiency thus represents a further T-cell deficiency predisposing to EV-specific HPVs.…”

The Mammalian Sterile 20–like 1 Kinase Controls Selective CCR7-Dependent Functions in Human Dendritic Cells

“…1). These results provide useful information to develop strategies to modulate selectively the functions of CCR7 in mDCs and to better interpret recently described pathologies associated with the loss of function of Mst1 (44)(45)(46).…”

“…Patients bearing mutations of Mst1 that lead to a loss in the function of this kinase show recurrent bacterial and viral infections and symptoms of autoimmunity (44)(45)(46). Resembling the phenotype observed in Mst1-deficient mice (25), these patients show also T cell lymphopenia and impaired T cell responses.…”

The non-canonical Hippo/Mst pathway in lymphocyte development and functions

“…Loss-of-function mutations of Mst1 in human patients have been identified in clinical studies [28,29,36]. MST1 deficiency in humans leads to T cell lymphopenia with a low proportion of naïve T cells and high proportion of effector T cells, impairment of T cell response to stimulation with anti-CD3, various mitogens and recall antigens [28].…”

“…It is also associated with neutropenia and heart malformations in some patients [29]. Mst1-deficient patients also display recurrent pulmonary infections, susceptibility to candidiasis and non-regressing cutaneous warts caused by multiple types of human papillomavirus infections [28,29,36]. These phenotypes have not been reported or observed in Mst1-deficient mice, probably as a result of the mice under SPF conditions.…”