The Phenotype of Human STK4 Deficiency

Abstract

692 Congenital neutropenia syndromes comprise a heterogeneous group of disorders, whose genetic etiology remains often unknown. We describe a consanguineous pedigree with several affected individuals characterized by predisposition to recurrent and chronic bacterial and viral infections. Affected patients had chronic bronchitis/bronchiectasis, recurrent bacterial and herpes simplex skin infections, and disseminated warts associated with human papillomavirus and molluscum contagiosum virus. One patient developed a lymphoproliferative disorder associated with EBV-infection. Patients had congenital neutropenia with fluctuating absolute neutrophil granulocyte counts (180-4000/μl), yet no evidence of cyclic neutropenia. Immunophenotyping of peripheral blood revealed a paucity of peripheral T- and B-cells. Interestingly all patients showed evidences of autoimmunity. In addition all affected patients had subtle and hemodynamically not relevant cardiac defects such as ASD-II (P1), patent foramen ovale (P2) and patent foramen ovale associated with mitral, tricuspid and pulmonary insufficiency (P3). Genome-wide genotyping and linkage analysis of the index family yielded a LOD score of 4.3 on a linkage interval on chromosome 20. Candidate gene sequencing revealed a homozygous nonsense mutation in exon 7 of the gene STK4 (formerly MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. Isolated STK4-deficient lymphocytes and neutrophils of these patients exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis in response to various proapoptotic stimuli. Lymphopenia and congenital neutropenia may therefore be a consequence of increased loss of peripheral lymphocytes and neutrophils, similar to other well defined monogenetic diseases of the immune system. STK4 deficiency is a novel human primary immunodeficiency syndrome and highlights the role of the HIPPO pathway for the development of the human immune and cardiac systems. Disclosures: No relevant conflicts of interest to declare.

Enhanced cytotoxic T‐cell function and inhibition of tumor progression by Mst1 deficiency

“…According to Choi et al [11], the death of Mst1 À/À T cells was due to oxidative stress and associated with decreased levels of FoxO1/3 activation and protein expression. Similar observations were also reported in humans [8,9].…”

“…Mst1 À/À mice exhibited impaired integrin-dependent processes including lymphocyte trafficking, antigen recognition and immunological tolerance [5][6][7]. Humans with MST1-null mutations exhibited immunodeficiency with autoimmune phenotypes [8,9]. In addition to germline mutations, the CpG island in the promoter of the human MST1 gene was found to be epigenetically down-regulated in patients with autoimmune pancreatitis [10].…”

“…Several recent studies of Mst1-deficient mammals reported accelerated apoptosis in thymocytes and peripheral T cells [8,9,[11][12][13]. According to Choi et al [11], the death of Mst1 À/À T cells was due to oxidative stress and associated with decreased levels of FoxO1/3 activation and protein expression.…”

Hippo vs. Crab: tissue‐specific functions of the mammalian Hippo pathway

“…In humans, mutations that inactivate MST1 are frequent in families with T-cell immunodeficiency and autoimmune disorders (Abdollahpour et al 2012; Genes to Cells (2017) 22, 6-31 Nehme et al 2012). SNPs in MST1 are linked to Crohn's disease (Waterman et al 2011;Nimmo et al 2012), a mutant phenotype also apparent in Mst1 KO mice (Zhou et al 2008;Dong et al 2009;Katagiri et al 2009;Ueda et al 2012;Du et al 2014), and (more severely) in Mst1/2 DKO mice (Mou et al 2012;Du et al 2014).…”

Primary immunodeficiencies and the control of Epstein–Barr virus infection

“…A similar broad susceptibility to infections is seen in another recently defined PID caused by homozygous mutations in the gene encoding the ubiquitously expressed serine-threonine kinase 4 (STK4), which is also known as mammalian sterile 20-like protein (MST1). 89,90 SKT4's role in immune cells is poorly defined, but its ability to phospho-rylate members of the FOXO transcription factor family can have multiple downstream effects. For example, in T cells, FOXO1 regulates the expression of the IL-7 receptor and of the lymphoid homing molecules CCR7 and CD62L.…”