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Case Reports
. 2012 Apr 12;119(15):3450-7.
doi: 10.1182/blood-2011-09-378158. Epub 2012 Jan 31.

VSports在线直播 - The phenotype of human STK4 deficiency

Hengameh Abdollahpour  1 , Giridharan Appaswamy, Daniel Kotlarz, Jana Diestelhorst, Rita Beier, Alejandro A Schäffer, E Michael Gertz, Axel Schambach, Hans H Kreipe, Dietmar Pfeifer, Karin R Engelhardt, Nima Rezaei, Bodo Grimbacher, Sabine Lohrmann, Roya Sherkat, Christoph Klein
Affiliations
Case Reports

The phenotype of human STK4 deficiency

Hengameh Abdollahpour et al. Blood. .

Abstract (VSports最新版本)

We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses VSports手机版. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome. .

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"VSports在线直播" Figures

Figure 1
Figure 1
Clinical phenotype of STK4-deficient patients. (A) H&E-stained bone marrow biopsy shows mild increase in cellularity and full maturation of neutrophil granulocytes. (B) The photograph shows disseminated warts infections in P2. (C) H&E-stained sections from wart biopsy shows orthokeratotic verrucosis and epithelial hyperplasia (P2; original magnification ×100). (D) Echocardiogram (P1) showing atrial septal defect type II (arrow) and left-right shunt. RA indicates right atrium; LA, left atrium; RV, right ventricle; and LV, left ventricle. (E) Giemsa staining of the enlarged inguinal lymph node of P3, showing accumulation of plasmacytoid differentiated cells (original magnification ×400).
Figure 2
Figure 2
Linkage analysis of index family, STK4 mutation, and absence of STK4 protein expression in the patients. (A) Pedigree of the family with SNP and microsatellite markers on chromosome 20. Gray shading represents the homozygous interval. Nomenclature of the persons in the text is as follows: II-1 indicates HET2; II-2, HET1; II-4, P1; II-5, P2; and III-1, P3. (B) Sanger sequencing of STK4 shows a nucleotide substitution G/A in exon 7, which leads to premature stop codon mutation. (C) Detection of STK4 protein in PBMCs by Western blot. All 3 STK4-deficient patients do not show any protein expression.
Figure 3
Figure 3
Immunophenotyping results of T and B cells in STK4-deficient patients. (A) Flow cytometric staining of peripheral CD3+CD4+ T cells for differentiation markers reveals relative increase of CD45RA−CD45RO+ memory T cells and decrease of CD45RA+CD45RO− naive T cells in PBMCs isolated from patients (P1, P2, and P3) compared with HD (healthy donors) and heterozygous. (B) Based on the expression of CD62L and CCR7, memory T cells were further divided into effector memory (CD45RO+CCR7−CD62L−) and central memory (CD45RO+CCR7+CD62L+) subsets. (C) The circulating B-cell pool was characterized by CD19 staining and further divided into B-cell subtypes. The immunophenotyping shows an increased fraction of transitional B cells (CD38++IgMhigh; D) and also reduction of marginal zone B cells (IgD+IgM+CD27+) and switched memory B cells (IgD−IgM−CD27+). The normal range for switched memory B cells in children 6 to 10 years of age is 5.2% to 12.1%; and for adults 19 to 25 years of age, it is 7.2% to 12.7%.
Figure 4
Figure 4
Functional studies of T lymphocytes and neutrophils. (A) Time course of induced apoptosis in STK4-deficient T cells on exposure to anti-Fas, which was measured by staining with annexin-V and propidium iodide. STK4-deficient T cells exhibited a significantly higher degree of apoptosis than did cells from control or heterozygous persons. (B) Time course of induced apoptosis in STK4 neutrophils on exposure to staurosporine. Patients' neutrophils showed increased apoptosis compared with healthy persons. (C) Visualization of gradual loss of mitochondrial membrane potential evidenced by fading CMXROS fluorescence intensity in T cells. Note that patients P1 and P2 have accelerated loss of Δψm compared with healthy control cells. (D) Enhanced loss of mitochondrial membrane potential Δψm in STK4-deficient neutrophil granulocytes, which is measured by fading JC-1 dye fluorescence intensity. (E) Decreased FOXO3 expression in PBMCs of STK4-deficient patients revealed by Western blot. Both the apoptosis and mitochondrial membrane potential assays were done twice, on independently purified cells.
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