SHORT Syndrome with Partial Lipodystrophy Due to Impaired Phosphatidylinositol 3 Kinase Signaling.

K.G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway
The American Journal of Human Genetics (Impact Factor: 10.99). 06/2013; DOI: 10.1016/j.ajhg.2013.05.023
Source: PubMed

ABSTRACT The phosphatidylinositol 3 kinase (PI3K) pathway regulates fundamental cellular processes such as metabolism, proliferation, and survival. A central component in this pathway is the p85α regulatory subunit, encoded by PIK3R1. Using whole-exome sequencing, we identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two unrelated families affected by partial lipodystrophy, low body mass index, short stature, progeroid face, and Rieger anomaly (SHORT syndrome). This mutation led to impaired interaction between p85α and IRS-1 and reduced AKT-mediated insulin signaling in fibroblasts from affected subjects and in reconstituted Pik3r1-knockout preadipocytes. Normal PI3K activity is critical for adipose differentiation and insulin signaling; the mutated PIK3R1 therefore provides a unique link among lipodystrophy, growth, and insulin signaling.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bruton's tyrosine kinase contains a pleckstrin homology domain, and it specifically binds inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), which is involved in the maturation of B cells. In this paper, we studied 12 systems including the wild type and 11 mutants, K12R, S14F, K19E, R28C/H, E41K, L11P, F25S, Y40N, and K12R-R28C/H, to investigate any change in the ligand binding site of each mutant. Molecular dynamics simulations combined with the method of molecular mechanics/Poisson-Boltzmann solvent-accessible surface area have been applied to the twelve systems, and reasonable mutant structures and their binding free energies have been obtained as criteria in the final classification. As a result, five structures, K12R, K19E, R28C/H, and E41K mutants, were classified as "functional mutations," whereas L11P, S14F, F25S, and Y40N were grouped into "folding mutations." This rigorous study of the binding affinity of each of the mutants and their classification provides some new insights into the biological function of the Btk-PH domain and related mutation-causing diseases.
    The Scientific World Journal 11/2013; 2013:580456. DOI:10.1155/2013/580456 · 1.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP3 as a signal for cell growth and proliferation, exist as an intracellular complex of a catalytic subunit bound to a regulatory subunit. We and others have previously reported that heterozygous mutations in PIK3CD encoding the p110δ catalytic PI3K subunit cause a unique disorder termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease. We report four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8(+) T cells toward terminally differentiated senescent effector cells with short telomeres. The PIK3R1 splice site mutation causes skipping of an exon, corresponding to loss of amino acid residues 434-475 in the inter-SH2 domain. The mutant p85α protein is expressed at low levels in patient cells and activates PI3K signaling when overexpressed in T cells from healthy subjects due to qualitative and quantitative binding changes in the p85α-p110δ complex and failure of the C-terminal region to properly inhibit p110δ catalytic activity.
    Journal of Experimental Medicine 12/2014; 211(13). DOI:10.1084/jem.20141759 · 13.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lipodystrophies are a genetically heterogeneous group of disorders characterized by loss of subcutaneous adipose tissue and metabolic dysfunction, including insulin resistance, increased levels of free fatty acids, abnormal adipocytokine secretion, and ectopic fat deposition, which are also observed in patients with visceral obesity and/or type 2 diabetes mellitus. Pathophysiological, biochemical, and genetic studies suggest that impairment in multiple adipose tissue functions, including adipocyte maturation, lipid storage, formation and/or maintenance of the lipid droplet, membrane composition, DNA repair efficiency, and insulin signaling, results in severe metabolic and endocrine consequences, ultimately leading to specific lipodystrophic phenotypes. In this review, recent evidences on the causes and metabolic processes of lipodystrophies will be presented, proposing a disease model that could be potentially informative for better understanding of common metabolic diseases in humans, including obesity, metabolic syndrome, and type 2 diabetes.
    Current Diabetes Reports 03/2015; 15(3):578. DOI:10.1007/s11892-015-0578-5 · 3.38 Impact Factor