Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.
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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.
SubjectHyper IgM syndrome
PIK3R1 splice site mutations
next generation sequencing
Published Version (Please cite this version)10.1007/s10875-016-0281-6
Publication InfoPetrovski, 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.
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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
Adjunct Professor in the Department of Molecular Genetics and Microbiology
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
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.
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
Professor of Pathology
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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