Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease.
Age Factors
Alleles
Child
Child, Preschool
Colonoscopy
Consanguinity
DNA Mutational Analysis
Female
Genetic Association Studies
Genetic Predisposition to Disease
Genotype
Humans
Immunohistochemistry
Inflammatory Bowel Diseases
/ diagnostic imaging
Loss of Function Mutation
Male
Microfilament Proteins
/ genetics
Pedigree
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
15 03 2021
15 03 2021
Historique:
received:
09
12
2020
accepted:
01
03
2021
entrez:
16
3
2021
pubmed:
17
3
2021
medline:
15
12
2021
Statut:
epublish
Résumé
CARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD.
Identifiants
pubmed: 33723309
doi: 10.1038/s41598-021-85399-9
pii: 10.1038/s41598-021-85399-9
pmc: PMC7960730
doi:
Substances chimiques
CARMIL1 protein, human
0
Microfilament Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5945Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK034854
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK118640
Pays : United States
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