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: 10.93). 06/2013; 93(1). 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.

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Available from: Ingfrid S Haldorsen, Sep 24, 2015
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    • "The absence of this deletion in his mother and sister and the lack of any SHORT syndrome phenotype in his father strongly suggest the occurrence of a de novo mutation in this patient. The second patient presents a mutation that is recurrent in other individuals with SHORT syndrome [5-8], which consists of a de novo heterozygous C > T transition at coding position 1945 of PIK3R1. This transition results in a change from arginine to tryptophan at position 649 of the mature protein. "
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    ABSTRACT: Background SHORT syndrome is a rare autosomal dominant condition whose name is the acronym of short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay (MIM 269880). Additionally, the patients usually present a low birth weight and height, lipodystrophy, delayed bone age, hernias, low body mass index and a progeroid appearance. Case presentation In this study, we used whole-exome sequencing approaches in two patients with clinical features of SHORT syndrome. We report the finding of a novel mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8), as well as a recurrent mutation c.1945C > T (p.Arg649Trp) in this gene. Conclusions We found a novel frameshift mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8) which consists of a deletion right before the site of substrate recognition. As a consequence, the protein lacks the position that interacts with the phosphotyrosine residue of the substrate, resulting in the development of SHORT syndrome.
    BMC Medical Genetics 05/2014; 15(1):51. DOI:10.1186/1471-2350-15-51 · 2.08 Impact Factor
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    • "Once the Btk-dependent signal transduction pathway is inactivated, B cells remain at the pre-B-cells stage leading to X-linked agammaglobulinemia (XLA) in humans, which is one of the most frequently inherited immunodeficient disorders in human, and X-linked immunodeficiency (Xid) in mice [5–8]. The Btk protein contains Src-homology 2 and 3 domains (SH2 and SH3), a catalytic SH1 domain, a Tec-homology (TH) domain, and an N-terminal pleckstrin homology (PH) domain [9] [10] [11]. Studies have shown that XLA mutations in Btk can be mapped to all five domains of the kinase, which are critical for signal transmission. "
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    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(3-4):580456. DOI:10.1155/2013/580456 · 1.73 Impact Factor
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    ABSTRACT: SHORT syndrome (OMIM 269880) is a rare autosomal dominant disorder characterized by short stature, hyperextensibility of joints, hernias, ocular depression, ophthalmic anomalies (Rieger anomaly, posterior embryotoxon, glaucoma), teething delay, partial lipodystrophy, insulin resistance and facial dysmorphic signs. Heterozygous mutations in PIK3R1 were recently identified in 14 families with SHORT syndrome. Eight of these families had a recurrent missense mutation (c.1945C>T; p.Arg649Trp). We report on two unrelated patients with typical clinical features of SHORT syndrome and additional problems such as pulmonary stenosis and ectopic kidney. Analysis of PIK3R1 revealed the mutation c.1945C>T; p.Arg649Trp de novo in both patients. These two patients not only provide additional evidence that PIK3R1 mutations cause SHORT syndrome, but also broaden the clinical spectrum of this syndrome and further confirm that the amino acid exchange c.1945C>T; p.Arg649Trp is a hotspot mutation in this gene.
    Clinical Genetics 08/2013; DOI:10.1111/cge.12263 · 3.93 Impact Factor
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