Novel frameshift variants expand the map of the genetic defects in IRF2BP2
García-Aznar, José María (Health in Code. Department of Immunology)
Maneiro Pampín, Emilia (Health in Code. Department of Immunology)
García Ramos, Maite (Health in Code. Department of Immunology)
Acuña Pérez, María José (Health in Code. Department of Immunology)
Paz Gandiaga, Nerea (Hospital Universitario Marqués de Valdecilla (Santander, Cantabria))
Minguell Domingo, Laura (Hospital Universitari Arnau de Vilanova)
Calavia, Olga (Hospital Universitari Joan XXIII de Tarragona)
Soler-Palacín, Pere (Hospital Universitari Vall d'Hebron)
Colobrán Oriol, Roger (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Novoa Bolívar, Erika M. (Hospital Universitario Virgen de la Arrixaca (Múrcia))
Ocejo Vinyals, Javier Gonzalo (Hospital Universitario Marqués de Valdecilla (Santander, Cantabria))

Data:	2023
Resum:	At present, the knowledge about disease-causing mutations in IRF2BP2 is very limited because only a few patients affected by this condition have been reported. As previous studies have described, the haploinsufficiency of this interferon transcriptional corepressors leads to the development of CVID. Very recently, a more accurate phenotype produced by truncating variants in this gene has been defined, manifesting CVID with gastrointestinal inflammatory symptoms and autoimmune manifestations. We analyzed 5 index cases with suspected primary immunodeficiency by high throughput sequencing. They were submitted for a genetic test with a panel of genes associated with immune system diseases, including IRF2BP2. The screening of SNVs, indels and CNVs fulfilling the criteria with very low allelic frequency and high protein impact, revealed five novel variants in IRF2BP2. In addition, we isolated both wild-type and mutated allele of the cDNA from one of the families. In this study, we report five novel loss-of-function (LoF) mutations in IRF2BP2 that likely cause primary immunodeficiency, with CVID as more frequent phenotype, variable expression of inflammatory gastrointestinal features, and one patient with predisposition of viral infection. All identified variants were frameshift changes, and one of them was a large deletion located on chromosome 1q42, which includes the whole sequence of IRF2BP2, among other genes. Both de novo and dominant modes of inheritance were observed in the families here presented, as well as incomplete penetrance. We describe novel variants in a delimited low-complex region, which may be considered a hotspot in IRF2BP2. Moreover, this is the first time that a large CNV in IRF2BP2 has been reported to cause CVID. The distinct mechanisms than LoF in IRF2BP2 could cause different phenotype compared with the mainly described. Further investigations are necessary to comprehend the regulatory mechanisms of IRF2BP2, which could be under variable expression of the disease.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	IRF2BP2 ; CVID ; Colitis ; Primary immunodeficiency ; Loss-of-function mutations
Publicat a:	Frontiers in immunology, Vol. 14 (October 2023) , art. 1279171, ISSN 1664-3224

DOI: 10.3389/fimmu.2023.1279171
PMID: 37876937

12 p, 3.7 MB

El registre apareix a les col·leccions:
Articles > Articles de recerca
Articles > Articles publicats