Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome.

Autor:	Ospina Cardona D; Center for Human Genetics and Genomics, New York University School of Medicine, New York, NY, USA., Rodriguez-Pinto I; Department of Internal Medicine, Hospital Mútua de Terrassa, Terrassa, Spain., Iosim S; Department of Pediatrics, New York University School of Medicine, New York, NY, USA., Bonet N; Genomics Core Facility, Departament de Medicina i Ciències de la Vida (MELIS), Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain., Mensa-Vilaro A; Department of Immunology, Hospital Clínic, Barcelona, Spain.; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain., Wong MK; Center for Human Genetics and Genomics, New York University School of Medicine, New York, NY, USA.; Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, USA., Ho G; Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, USA., Tormo M; Genomics Core Facility, Departament de Medicina i Ciències de la Vida (MELIS), Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.; Scientific Computing Core Facility, Departament de Medicina i Ciències de la Vida (MELIS), Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain., Yagüe J; Department of Immunology, Hospital Clínic, Barcelona, Spain.; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.; School of Medicine, Universitat de Barcelona, Barcelona, Spain., Shon W; Department Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Wallace DJ; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Casals F; Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain., Beck DB; Center for Human Genetics and Genomics, New York University School of Medicine, New York, NY, USA.; Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, USA.; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA., Abuav R; Department Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Arostegui JI; Department of Immunology, Hospital Clínic, Barcelona, Spain.; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.; School of Medicine, Universitat de Barcelona, Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	Rheumatology (Oxford, England) [Rheumatology (Oxford)] 2024 Oct 01; Vol. 63 (10), pp. 2897-2902.
DOI:	10.1093/rheumatology/keae201
Abstrakt:	Objective: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a complex immune disorder consequence of somatic UBA1 variants. Most reported pathogenic UBA1 variants are missense or splice site mutations directly impairing the translational start site at p.Met41, with recent studies showing that these variants are frequent causes of recurrent inflammation in older individuals. Here we aimed to characterize a novel UBA1 variant found in two patients clinically presenting with VEXAS syndrome. Methods: Patients' data were collected from direct assessments and from their medical charts. Genomics analyses were undertaken by both Sanger and amplicon-based deep sequencing, and mRNA studies were undertaken by both cDNA subcloning and mRNA sequencing. Results: We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung inflammation responsive only to glucocorticoids. RNA analysis of the patients' samples indicated aberrant mRNA splicing leading to multiple in-frame transcripts, including a transcript retaining the full sequence of intron 4 and a different transcript with the deletion of the first 15 nucleotides of exon 5. Conclusion: Here we describe abnormal UBA1 transcription as a consequence of the novel c.346-2A>G variant, identified in two patients with clinical features compatible with VEXAS syndrome. Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and provide support for a complete gene evaluation in those patients considered candidates for VEXAS syndrome. (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
Databáze:	MEDLINE
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