The molecular mechanisms that underlie T-cell quiescence are poorly understood. In the present study, we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily char-
IntroductionThe study of human T-cell primary immunodeficiencies has enabled the molecular characterization of many diseases caused by Mendelian inheritance of mutated genes [1][2][3][4] and has revealed the function of key molecules in T-cell biology. SCIDs are characterized by complete lack of T-cell development and, in some conditions, developmental blocks on other lymphoid lineages. 1,2 Several mechanisms can leads to faulty T-cell differentiation, such as the premature death of progenitor cells and impaired ␥c-dependent cytokine signaling, VDJ recombination, or pre-TCR signaling. 1 In other forms of T-cell primary immunodeficiency, TCR-mediated T-cell activation is defective but T-cell differentiation is partially or fully preserved. The latter variously include deficiencies in DOCK8, ZAP-70, ITK, ORA1, and STIM-1, all of which are involved in the signaling cascade downstream of the TCR, and in molecules involved in the NFB pathway, such as NEMO and IKB␣. 2,5,6 These conditions are collectively referred to as combined immunodeficiencies (CIDs), because the functional consequences also include defective Ab production.The molecular signatures of many more T-cell immunodeficiency phenotypes have yet to be identified. In the present study, we describe a new form of human CID observed in 4 patients from 2 families that is primarily characterized by a dramatically reduced pool of circulating naive T cells and impaired in vitro survival of the T-lymphocyte population. These patients were shown to carry homozygous mutations in the serine-threonine protein kinase 4 (STK4) gene, coding for the ubiquitously expressed mammalian sterile 20-like protein MST1.
Methods
Case reportsPatient F1P1 was born to a consanguineous family of Turkish origin (see Figure 1A). Since the age of 2, he had suffered from recurrent skin and lower respiratory tract infections caused by Streptococcus pneumoniae and Haemophilus influenzae, leading to bronchiectasis, recurrent perioral herpes simplex infections with positive anti-HSV1-2 IgG titer, Varicella zoster virus (VZV) infections, and extensive molluscum contagiosum. In addition, the patient had chronic EBV infection with persistent EBV viremia (53 000 copies/mL at the age of 11 years) and positive anti-EBNA-1 and anti-VCA IgG Ab. At the age of 5, patient F1P1 was successfully treated for EBV ϩ Hodgkin B-cell lymphoma. The patient (now 17) is receiving Ig replacement therapy and anti-infective prophylaxis with antibiotics and antivirals. Apart from lymphocytopenia, his blood counts are consistently normal. A CT scan of the thymus performed at 11 years of age was normal in appearance, structure, and size compared with agematched controls. He has no dysmorphic syndrome and his growth was within the normal range.Family F2 is consanguineous and of Turkish origin, with 3 children affected ( Figu...
