Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma

Journal of Clinical Immunology
Ido SomekhRaz Somech

Abstract

RAS guanyl-releasing protein 1 (RASGRP1) deficiency has recently been shown to cause a primary immunodeficiency (PID) characterized by CD4+ T cell lymphopenia and Epstein-Barr virus (EBV)-associated B cell lymphoma. Our report of three novel patients widens the scope of RASGRP1 deficiency by providing new clinical and immunological insights on autoimmunity, immune cell development, and predisposition to lymphoproliferative disease. One patient of Turkish origin (P1) and two Palestinian patients (P2, P3) were evaluated for immunodeficiency. To decipher the molecular cause of disease, whole exome sequencing was conducted. Identified mutations were validated by immunological and biochemical assays. We report three patients presenting with similar clinical characteristics of immunodeficiency and EBV-associated lymphoproliferative disease. In addition, P2 and P3 exhibited overt autoimmune manifestations. Genetic screening identified two novel loss-of-function mutations in RASGRP1. Immunoblotting and active Ras pull-down assays confirmed perturbed ERK1/2 signaling and reduced Ras-GTPase activity in heterologous Jurkat cells with ectopic expression of RASGRP1 mutants. All three patients had CD4+ T cell lymphopenia. P2 and P3 showed de...Continue Reading

References

Dec 9, 1997·Immunity·L L SharpS M Hedrick
Mar 23, 2001·Nature Immunology·N A DowerJ C Stone
May 30, 2002·Nature Reviews. Immunology·Ronald N Germain
Dec 31, 2003·Nature Immunology·Alain Fischer
Feb 19, 2004·The Journal of Biological Chemistry·Benoit Guilbault, Robert J Kay
Jan 22, 2005·Immunological Reviews·Gael MénaschéGeneviève de Saint Basile
Nov 23, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jason J CoughlinJames C Stone
Oct 21, 2006·Biochemical Society Transactions·J C Stone
Sep 20, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Shinsuke YasudaTakao Koike
Nov 26, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Suk Hyung LeeInpyo Choi
Jan 1, 2010·The Journal of Allergy and Clinical Immunology·Luigi D Notarangelo
Oct 6, 2011·Current Opinion in Allergy and Clinical Immunology·Raz Somech
May 25, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yong ChenXiao-Ping Zhong
Dec 12, 2012·The Journal of Allergy and Clinical Immunology·Atar LevRaz Somech
Jan 15, 2013·Current Protocols in Human Genetics·Ivan AdzhubeiShamil R Sunyaev
Jun 14, 2013·British Journal of Haematology·Nima ParvanehArndt Borkhardt
Sep 3, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Amber BartlettRobert A Barrington
Aug 26, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Véronique Minard-ColinCatherine Patte
Sep 29, 2015·Annals of the New York Academy of Sciences·Umaimainthan Palendira, Alan B Rickinson
Dec 31, 2015·Arthritis Research & Therapy·Marie-Laure GolinskiThierry Lequerré
Jun 10, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Andrew FerrettiRobert A Barrington
Nov 1, 2016·Nature Immunology·Elisabeth SalzerKaan Boztug
Nov 3, 2016·Scientific Reports·Xu-Jie ZhouHong Zhang
Feb 1, 2017·Genome Biology·Mark I McCarthy, Daniel G MacArthur
Jul 1, 2017·Cell·Dhirendra K SimanshuFrank McCormick
Aug 10, 2017·Frontiers in Immunology·Michael SelemanJanet Chou
Nov 21, 2017·The Journal of Allergy and Clinical Immunology·Huawei MaoYu-Lung Lau
Dec 29, 2017·EMBO Molecular Medicine·Sarah WinterSylvain Latour
Feb 28, 2018·Nature Genetics·Daniel KotlarzChristoph Klein

❮ Previous
Next ❯

Citations

Jan 25, 2020·Current Opinion in Rheumatology·Rodrigo Hoyos-Bachiloglu, Janet Chou
Sep 19, 2019·Current Pediatric Reviews·Rejin KebudiMerve K Sahin
Oct 4, 2019·Leukemia & Lymphoma·Mathilde HerberAurélien Guffroy
Mar 5, 2021·Frontiers in Immunology·Shiva Pathak, Everett H Meyer
May 15, 2021·Current Opinion in Immunology·Benjamin Fournier, Sylvain Latour
May 20, 2021·Clinical and Experimental Immunology·Giorgio Costagliola, Rita Consolini
Aug 31, 2021·Frontiers in Immunology·Yael Dinur-SchejterPolina Stepensky
Jan 13, 2022·Clinical Reviews in Allergy & Immunology·Margaret T RedmondBenjamin T Prince

❮ Previous
Next ❯

Datasets Mentioned

BETA
BC109297

Methods Mentioned

BETA
flow cytometry
PCR
transfection
Pull-Down
GTPase
biopsy
exome sequencing
Phenotyping
PMA

Software Mentioned

Prism
GraphPad
HighV
Polymorphism Phenotyping ( PolyPhen -

Related Concepts

Related Feeds

B cells: Gene Expression

B lymphocytes are white blood cells that play a role in the adaptive immune system by secreting antibodies. Here is the latest research on gene expression in B cells.

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.

CRISPR (general)

Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). CRISPR-Cas system enables the editing of genes to create or correct mutations. Discover the latest research on CRISPR here.

CRISPR for Genome Editing

Genome editing technologies enable the editing of genes to create or correct mutations. Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). Here is the latest research on the use of CRISPR-Cas system in gene editing.

B-Cell Leukemia (Keystone)

B-cell leukemia includes various types of lymphoid leukemia that affect B cells. Here is the latest research on B-cell leukemia.

Autoimmune Lymphoproliferative Syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis. Discover the latest research on ALPS here.

CRISPR in Cancer

CRISPR-Cas system enables the editing of genes to create or correct mutations. Given that genome instability and mutation is one of the hallmarks of cancer, the CRISPR-Cas system is being explored to genetically alter and eliminate cancer cells. Here is the latest research.

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.

B-Cell Lymphoma

B-cell lymphomas include lymphomas that affect B cells. This subtype of cancer accounts for over 80% of non-Hodgkin lymphomas in the US. Here is the latest research.