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

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Date
2016-07
Authors
Petrovski, Slavé
Parrott, Roberta E
Roberts, Joseph L
Huang, Hongxiang
Yang, Jialong
Gorentla, Balachandra
Mousallem, Talal
Wang, Endi
Armstrong, Martin
McHale, Duncan
MacIver, Nancie J
Goldstein, David B
Zhong, Xiao-Ping
Buckley, Rebecca H
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Abstract
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.
Type
Journal article
Subject
Hyper IgM syndrome
PIK3R1 splice site mutations
SHORT syndrome
lymphadenopathy
mTOR pathway
next generation sequencing
short stature
Permalink
https://hdl.handle.net/10161/11947
Published Version (Please cite this version)
10.1007/s10875-016-0281-6
Publication Info
Petrovski, Slavé; Parrott, Roberta E; Roberts, Joseph L; Huang, Hongxiang; Yang, Jialong; Gorentla, Balachandra; ... Buckley, Rebecca H (2016). Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature. J Clin Immunol, 36(5). pp. 462-471. 10.1007/s10875-016-0281-6. Retrieved from https://hdl.handle.net/10161/11947.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Buckley

Rebecca Hatcher Buckley

James Buren Sidbury Distinguished Professor of Pediatrics, in the School of Medicine
The overall emphasis of Dr. Buckley's research is in human T,B and NK cell development and in aberrations in their development and regulation. The work involves three particular areas of investigation: 1) the cellular and molecular bases of genetically-determined human immunodeficiency diseases, 2) the use of bone marrow stem cells to cure genetically-determined immunodeficiency diseases, and 3) the use of human SCID bone marrow stem cell chimeras to study human thymic education, T and B cell on

David Benjamin Goldstein

Adjunct Professor in the Department of Molecular Genetics and Microbiology
MacIver

Nancie Jo MacIver

Adjunct Associate Professor in the Department of Pediatrics
My laboratory is broadly interested in how large changes in nutritional status (e.g. malnutrition or obesity) influence T cell immunity.  Malnutrition can lead to immunodeficiency and increased risk of infection, whereas obesity is associated with inflammation that promotes multiple diseases including autoimmunity, type 2 diabetes, and cardiovascular disease.  We have identified the adipocyte-secreted hormone leptin as a critical link between nutrition and immunity.  Leptin is
Mousallem

Talal Imad Mousallem

Associate Professor of Pediatrics
I am an allergist and immunologist who cares for children. I manage patients with primary immunodeficiency and different allergic diseases. This includes managing patients with recurrent infections, allergic rhinitis, asthma, food allergy, drug allergy, stinging insect hypersensitivity, urticaria/ angioedema, and allergic skin disease. I also see patients with abnormal severe combined immunodeficiency newborn screen results.
Roberts

Joseph Linton Roberts

Professor Emeritus of Pediatrics
My overall research interests are studying T cell development and defining the molecular bases of inherited immunodeficiency diseases. We are using standard candidate gene analysis approaches as well as new high throughput genome-wide sequencing, bioinformatics and functional screening in zebrafish and murine models in our work. Using these strategies we have recently reported a new molecular etiology of severe combined immunodeficiency (SCID), CD3 zeta chain deficiency. In collaboration w
Wang

Endi Wang

Professor of Pathology
Zhong

Xiaoping Zhong

Professor of Pediatrics
The immune system protects the host from microbial infection but can cause diseases if not properly controlled. My lab is interested in the receptor signaling mediated regulation of immune cell development and function as well as the pathogenesis and treatment of autoimmune diseases and allergies. We are currently investigating the roles diacylglycerol kinases (DGKs) and TSC1/2-mTOR play in the immune system. DGKs are a family of ten enzymes that catalyze the conversion of diacylgl
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