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


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.





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Publication Info

Petrovski, Slavé, Roberta E Parrott, Joseph L Roberts, Hongxiang Huang, Jialong Yang, Balachandra Gorentla, Talal Mousallem, Endi Wang, et al. (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

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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 with Dr. Wesley Burks we are also examining changes in T cell transcription patterns following treatment for peanut allergy using genome wide oligonucleotide microarrays.


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.


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 diacylglycerol (DAG) to phosphatidic acid (PA), Both DAG and PA are important second messengers involved signaling from numerous receptors. While we expect DGKs to perform important roles in development and cellular function by modulating DAG and PA levels, the physiologic functions of DGKs have been poorly understood. Using cell line models and genetically manipulated mice, we have demonstrated that DGKα and ζ isoforms play critical roles in: T cell development, activation, and anergy by regulating T cell receptor signaling; FcεRI signaling and mast cell function; and Toll-like receptor signaling and innate immune responses.

Research areas that we are actively pursuing include:
1. The mechanisms that control T cell maturation, activation
and self-tolerance.
2. NKT cell development and function.
3. Thymic epithelial cells and thymic development, function, and involution.
4. Regulation of Toll-like receptor signaling and innate immunity. 
5. The pathogenesis and treatment of autoimmune hepatitis. 
6. Mast cell development and function.
7. The pathogenesis and immunotherapy for peanut allergy.


Rebecca Hatcher Buckley

James Buren Sidbury Distinguished Professor Emeritus 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 ontogeny, tolerance induction and MHC restriction mechanisms. Methodology includes monoclonal antibody (mAb) analyses of lymphocyte phenotypes, a variety of T cell and natural killer (NK) cell functional assays, studies of thymic output by T cell receptor recombination excision circle measurement, studies of T cell diversity by spectratyping, studies of T cell longevity by telomere analysis and assessment of B cell differentiation and function. A unique resource available for her studies is the largest population of patients with genetically-determined immunodeficiency diseases in the U.S., which includes the largest population in the world of longterm SCID chimeras treated at a single center, some of whom have been studied and followed for more than 37 years. The administration of rigorously T cell depleted haploidentical bone marrow stem cells to SCID recipients without pre-transplant conditioning or post-transplant use of immunosuppressive drugs to prevent GVHD provides an unmanipulated system for studying human thymic education, T and B cell ontogeny, MHC restriction mechanisms and tolerance induction. Studies to identify mutations in patients with primary immunodeficiency are continuing, particularly in those with SCID.

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