Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.
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 articleSubject
Hyper IgM syndromePIK3R1 splice site mutations
SHORT syndrome
lymphadenopathy
mTOR pathway
next generation sequencing
short stature
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https://hdl.handle.net/10161/11947Published Version (Please cite this version)
10.1007/s10875-016-0281-6Publication 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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Show full item recordScholars@Duke
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
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
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.
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
Endi Wang
Professor of Pathology
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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