Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.

Frontiers in Immunology
Anas M AlazamiHamoud Al-Mousa

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 elect...Continue Reading

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Citations

Mar 4, 2020·Annual Review of Immunology·Joshua D Milner
Sep 7, 2018·Current Opinion in Allergy and Clinical Immunology·Mark J PonsfordAdam Klocperk
Jul 11, 2018·Frontiers in Immunology·Cristiane de Jesus Nunes-Santos, Sergio D Rosenzweig
May 23, 2019·Inflammatory Bowel Diseases·Thomas MaggDaniel Kotlarz
Jan 23, 2020·Journal of Clinical Immunology·Stephanie HellerHorst von Bernuth
Jul 26, 2018·Allergy·Mark J PonsfordStephen Jolles
Oct 10, 2018·Current Opinion in Pediatrics·Joyce E YuYesim Yilmaz Demirdag
Mar 12, 2019·The Journal of Clinical Investigation·Nurit P Azouz, Marc E Rothenberg
Nov 13, 2020·Frontiers in Cell and Developmental Biology·Youngjin ParkViswanath Kiron
Aug 8, 2021·Current Opinion in Immunology·Vivien Béziat, Emmanuelle Jouanguy
Aug 15, 2021·Journal of Clinical Immunology·Natalie FredeBodo Grimbacher
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Jan 13, 2022·Clinical Reviews in Allergy & Immunology·Margaret T RedmondBenjamin T Prince

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Datasets Mentioned

BETA
E-MTAB-6440
PRJEB24299

Methods Mentioned

BETA
exome sequencing
Genotyping
PCR
Protein Assay
flow cytometry

Software Mentioned

FACSDiva
MODEL
ExAC Browser
SWISS
Exome
AutoSNPa
BD

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