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

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

Netherlands

2016-05-01T14:02:48Z

2016-07

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.

http://www.ncbi.nlm.nih.gov/pubmed/27076228

10.1007/s10875-016-0281-6

1573-2592

https://hdl.handle.net/10161/11947

eng

Springer Science and Business Media LLC

J Clin Immunol

10.1007/s10875-016-0281-6

Hyper IgM syndrome

PIK3R1 splice site mutations

SHORT syndrome

lymphadenopathy

mTOR pathway

next generation sequencing

short stature

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

Journal article

MacIver, Nancie J|0000-0003-3676-9391

Buckley, Rebecca H|0000-0002-6914-346X

http://www.ncbi.nlm.nih.gov/pubmed/27076228

462

471

5

Basic Science Departments

Clinical Science Departments

Duke

Duke Cancer Institute

Immunology

Institutes and Centers

Pediatrics

Pediatrics, Allergy and Immunology

Pediatrics, Endocrinology

Pharmacology & Cancer Biology

School of Medicine

Published

36