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

dc.contributor.author Armstrong, M
dc.contributor.author Buckley, Rebecca Hatcher
dc.contributor.author Goldstein, David Benjamin
dc.contributor.author Gorentla, B
dc.contributor.author Huang, H
dc.contributor.author MacIver, Nancie Jo
dc.contributor.author McHale, D
dc.contributor.author Mousallem, T
dc.contributor.author Parrott, RE
dc.contributor.author Petrovski, S
dc.contributor.author Roberts, JL
dc.contributor.author Wang, Endi
dc.contributor.author Yang, J
dc.contributor.author Zhong, XP
dc.coverage.spatial Netherlands
dc.date.accessioned 2016-05-01T14:02:48Z
dc.date.issued 2016-07
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/27076228
dc.identifier 10.1007/s10875-016-0281-6
dc.identifier.uri https://hdl.handle.net/10161/11947
dc.description.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.
dc.language eng
dc.relation.ispartof J Clin Immunol
dc.relation.isversionof 10.1007/s10875-016-0281-6
dc.subject Hyper IgM syndrome
dc.subject PIK3R1 splice site mutations
dc.subject SHORT syndrome
dc.subject lymphadenopathy
dc.subject mTOR pathway
dc.subject next generation sequencing
dc.subject short stature
dc.title Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/27076228
pubs.begin-page 462
pubs.end-page 471
pubs.issue 5
pubs.organisational-group Basic Science Departments
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Immunology
pubs.organisational-group Institutes and Centers
pubs.organisational-group Pediatrics
pubs.organisational-group Pediatrics, Allergy and Immunology
pubs.organisational-group Pediatrics, Endocrinology
pubs.organisational-group Pharmacology & Cancer Biology
pubs.organisational-group School of Medicine
pubs.publication-status Published
pubs.volume 36
dc.identifier.eissn 1573-2592


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