Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency
Open Access
- 9 February 2018
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Immunology
- Vol. 9, 203
- https://doi.org/10.3389/fimmu.2018.00203
Abstract
Combined immunodeficiencies are a heterogeneous collection of primary immune disorders that exhibit defects in T cell development or function, along with impaired B cell activity even in light of normal B cell maturation. CARMIL2 (RLTPR) is a protein involved in cytoskeletal organization and cell migration, which also plays a role in CD28 co-signaling of T cells. Mutations in this protein have recently been reported to cause a novel primary immunodeficiency disorder with variable phenotypic presentations. Here, we describe seven patients from three unrelated, consanguineous multiplex families that presented with dermatitis, esophagitis, and recurrent skin and chest infections with evidence of combined immunodeficiency. Through the use of whole exome sequencing and autozygome-guided analysis, we uncovered two mutations not previously reported (p.R50T and p.L846Sfs) in CARMIL2. Real-time PCR analysis revealed that the biallelic frameshift mutation is under negative selection, likely due to nonsense-mediated RNA decay and leading to loss of detectable protein upon immunoblotting. Protein loss was also observed for the missense mutation, and 3D modeling suggested a disturbance in structural stability due to an increase in the electrostatic energy for the affected amino acid and surrounding residues. Immunophenotyping revealed that patient Treg counts were significantly depressed, and that CD4+ T cells were heavily skewed towards the naïve status. CD3/CD28 signaling impairment was evidenced by reduced proliferative response to stimulation. This work broadens the allelic heterogeneity associated with CARMIL2 and highlights a deleterious missense alteration located outside the leucine-rich repeat of the protein, where all other missense mutations have been reported to date.Keywords
Funding Information
- King Abdulaziz City for Science and Technology (KACST 14-MED316-20)
This publication has 21 references indexed in Scilit:
- A human immunodeficiency syndrome caused by mutations in CARMIL2Nature Communications, 2017
- Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutationsThe Journal of Experimental Medicine, 2016
- A potential founder variant inCARMIL2/RLTPRin three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunctionMolecular Genetics & Genomic Medicine, 2016
- Severe combined immunodeficiencies and related disordersNature Reviews Disease Primers, 2015
- Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015Journal of Clinical Immunology, 2015
- Primary Immunodeficiency Diseases in Saudi Arabia: a Tertiary Care Hospital Experience over a Period of Three Years (2010–2013)Journal of Clinical Immunology, 2015
- Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseasesGenome Biology, 2015
- Combined immunodeficiency: The Middle East experienceJournal of Allergy and Clinical Immunology, 2013
- Defining combined immunodeficiencyJournal of Allergy and Clinical Immunology, 2012
- Clinical and immunological manifestations of patients with atypical severe combined immunodeficiencyClinical Immunology, 2011