Skip to main content
Journal cover image

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

Publication ,  Journal Article
Petrovski, S; Parrott, RE; Roberts, JL; Huang, H; Yang, J; Gorentla, B; Mousallem, T; Wang, E; Armstrong, M; McHale, D; MacIver, NJ ...
Published in: J Clin Immunol
July 2016

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Clin Immunol

DOI

EISSN

1573-2592

Publication Date

July 2016

Volume

36

Issue

5

Start / End Page

462 / 471

Location

Netherlands

Related Subject Headings

  • Thorax
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Ribosomal Protein S6 Kinases
  • Phosphatidylinositol 3-Kinases
  • Nephrocalcinosis
  • Neck
  • Mutation
  • Metabolic Diseases
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Petrovski, S., Parrott, R. E., Roberts, J. L., Huang, H., Yang, J., Gorentla, B., … Buckley, R. H. (2016). Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature. J Clin Immunol, 36(5), 462–471. https://doi.org/10.1007/s10875-016-0281-6
Petrovski, Slavé, Roberta E. Parrott, Joseph L. Roberts, Hongxiang Huang, Jialong Yang, Balachandra Gorentla, Talal Mousallem, et al. “Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.J Clin Immunol 36, no. 5 (July 2016): 462–71. https://doi.org/10.1007/s10875-016-0281-6.
Petrovski S, Parrott RE, Roberts JL, Huang H, Yang J, Gorentla B, et al. Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature. J Clin Immunol. 2016 Jul;36(5):462–71.
Petrovski, Slavé, et al. “Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.J Clin Immunol, vol. 36, no. 5, July 2016, pp. 462–71. Pubmed, doi:10.1007/s10875-016-0281-6.
Petrovski S, Parrott RE, Roberts JL, Huang H, Yang J, Gorentla B, Mousallem T, Wang E, Armstrong M, McHale D, MacIver NJ, Goldstein DB, Zhong X-P, Buckley RH. Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature. J Clin Immunol. 2016 Jul;36(5):462–471.
Journal cover image

Published In

J Clin Immunol

DOI

EISSN

1573-2592

Publication Date

July 2016

Volume

36

Issue

5

Start / End Page

462 / 471

Location

Netherlands

Related Subject Headings

  • Thorax
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Ribosomal Protein S6 Kinases
  • Phosphatidylinositol 3-Kinases
  • Nephrocalcinosis
  • Neck
  • Mutation
  • Metabolic Diseases
  • Male