PI3-kinase mutation linked to insulin and growth factor resistance in vivo

Winnay, Jonathon N.; Solheim, Marie H.; Dirice, Ercument; Sakaguchi, Masaji; Noh, Hye Lim; Kang, Hee Joon; Takahashi, Hirokazu; Chudasama, Kishan; Kim, Jason K.; Molven, Anders; Kahn, C. Ronald; Njølstad, Pål R.

doi:10.1172/jci84005

Cited by 61 publications

(67 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It also suggests that the p85α Δ434_475 mutation may affect other catalytic PI3K sub-units such as PIK3CA that are known to be important for insulin receptor signaling [25]. It is important to note that some SHORT syndrome patients with mutations in exon 14 [11–14] and a murine model mimicking one of the PIK3R1 mutations [26] displayed impaired PI3K signaling. Studies have demonstrated that chronic overactivation of signal pathways can lead impairment of receptor induced signaling [27].…”

Section: Discussionmentioning

confidence: 99%

Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature

et al. 2016

View full text Add to dashboard Cite

The purpose of this research was to use next generation sequencing to identify mutations in patients with primary immunodeficiency diseases whose pathogenic gene mutations had not been identified. Remarkably, four unrelated patients were found by next generation sequencing to have the same heterozygous mutation in an essential donor splice site of PIK3R1 (NM_181523.2:c.1425 + 1G > A) found in three prior reports. All four had the Hyper IgM syndrome, lymphadenopathy and short stature, and one also had SHORT syndrome. They were investigated with in vitro immune studies, RT-PCR, and immunoblotting studies of the mutation's effect on mTOR pathway signaling. All patients had very low percentages of memory B cells and class-switched memory B cells and reduced numbers of naïve CD4+ and CD8+ T cells. RT-PCR confirmed the presence of both an abnormal 273 base-pair (bp) size and a normal 399 bp size band in the patient and only the normal band was present in the parents. Following anti-CD40 stimulation, patient's EBV-B cells displayed higher levels of S6 phosphorylation (mTOR complex 1 dependent event), Akt phosphorylation at serine 473 (mTOR complex 2 dependent event), and Akt phosphorylation at threonine 308 (PI3K/PDK1 dependent event) than controls, suggesting elevated mTOR signaling downstream of CD40. These observations suggest that amino acids 435–474 in PIK3R1 are important for its stability and also its ability to restrain PI3K activity. Deletion of Exon 11 leads to constitutive activation of PI3K signaling. This is the first report of this mutation and immunologic abnormalities in SHORT syndrome.

show abstract

Section: Discussionmentioning

confidence: 99%

Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature

et al. 2016

View full text Add to dashboard Cite

show abstract

“…13 Resistance to other growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) has not yet been studied but is very likely, and this would have an important impact on events such as embryonic development, cell migration, and angiogenesis. Thus, it is not surprising that homozygous Arg649Trp mutant animals are embryonic lethal, while the heterozygous knock-in animals show features of SHORT syndrome such as lipodystrophy and insulin resistance and reduced overall body weight and growth, as well as iris malformations.…”

Section: Discussionmentioning

confidence: 99%

“…13 All animal experiments were approved by and conducted in accordance with guidelines established by the Institutional Animal Care and Use Committee at the Joslin Diabetes Center and adhered to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.…”

Section: Methodsmentioning

confidence: 99%

Iris Malformation and Anterior Segment Dysgenesis in Mice and Humans With a Mutation in PI 3-Kinase

Solheim

Clermont

Winnay

et al. 2017

Invest. Ophthalmol. Vis. Sci.

Self Cite

View full text Add to dashboard Cite

PurposeTo determine the ocular consequences of a dominant-negative mutation in the p85α subunit of phosphatidylinositol 3-kinase (PIK3R1) using a knock-in mouse model of SHORT syndrome, a syndrome associated with short stature, lipodystrophy, diabetes, and Rieger anomaly in humans.MethodsWe investigated knock-in mice heterozygous for the SHORT syndrome mutation changing arginine 649 to tryptophan in p85α (PIK3R1) using physical examination, optical coherence tomography (OCT), tonometry, and histopathologic sections from paraffin-embedded eyes, and compared the findings to similar investigations in two human subjects with SHORT syndrome heterozygous for the same mutation.ResultsWhile overall eye development was normal with clear cornea and lens, normal anterior chamber volume, normal intraocular pressure, and no changes in the retinal structure, OCT images of the knock-in mouse eyes revealed a significant decrease in thickness and width of the iris resulting in increased pupil area and irregularity of shape. Both human subjects had Rieger anomaly with similar defects including thin irides and irregular pupils, as well as a prominent ring of Schwalbe, goniosynechiae, early cataract formation, and glaucoma. Although the two subjects had had diabetes for more than 30 years, there were no signs of diabetic retinopathy.ConclusionsA dominant-negative mutation in the p85α regulatory subunit of PI3K affects development of the iris, and contributes to changes consistent with anterior segment dysgenesis in both humans and mice.

show abstract

“…Repressions of these vital signaling proteins by PHLPP, 'switch off' the action and act as an important player for specific and dynamic regulation in mammalian cells. Overexpression/genetic mutation in the PI3K gene or disturbance in its regulatory components leads to insulin resistance (Schultze et al 2012, Winnay et al 2016. The alterations brought about in PKC, GSK3β and their downstream targets correspond to the pathogenicity observed during diabetes including oxidative stress (Gerber & Rutter 2017), mitochondrial dysfunction (Peiris et al 2016), impaired glucose metabolism (Aguayo et al 2016), aberrant autophagy (Quan et al 2012) and cell death (Hwang et al 2015).…”

Section: Phlpp Mediates Cellular Events Leading To Diabetic Risksmentioning

confidence: 99%

PHLPP: a putative cellular target during insulin resistance and type 2 diabetes

Mathur

Pandey

Kakkar

2017

Journal of Endocrinology

View full text Add to dashboard Cite

Progressive research in the past decade converges to the impact of PHLPP in regulating the cellular metabolism through PI3K/AKT inhibition. Aberrations in PKB/AKT signaling coordinates with impaired insulin secretion and insulin resistance, identified during T2D, obesity and cardiovascular disorders which brings in the relevance of PHLPPs in the metabolic paradigm. In this review, we discuss the impact of PHLPP isoforms in insulin signaling and its associated cellular events including mitochondrial dysfunction, DNA damage, autophagy and cell death. The article highlights the plausible molecular targets that share the role during insulin-resistant states, whose understanding can be extended into treatment responses to facilitate targeted drug discovery for T2D and allied metabolic syndromes.

show abstract

PI3-kinase mutation linked to insulin and growth factor resistance in vivo

Cited by 61 publications

References 48 publications

Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature

Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature

Iris Malformation and Anterior Segment Dysgenesis in Mice and Humans With a Mutation in PI 3-Kinase

PHLPP: a putative cellular target during insulin resistance and type 2 diabetes

Contact Info

Product

Resources

About