DNASE1L3 Mutations in Hypocomplementemic Urticarial Vasculitis Syndrome

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 65; no. 8; pp. 2183 - 2189
• Main Authors: Özçakar, Z. Birsin, Foster, Joseph, Diaz‐Horta, Oscar, Kasapcopur, Ozgur, Fan, Yao‐Shan, Yalçınkaya, Fatoş, Tekin, Mustafa
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2013
• Subjects: Age of Onset; Autoimmune diseases; Child; Child, Preschool; Complement System Proteins - deficiency; DNA Mutational Analysis; Endodeoxyribonucleases - genetics; Female; Genes, Recessive; Humans; Immune System Diseases - diagnosis; Immune System Diseases - genetics; Immune System Diseases - immunology; Male; Mutation; Pathogenesis; Urticaria - diagnosis; Urticaria - genetics; Urticaria - immunology; Vasculitis - diagnosis; Vasculitis - genetics; Vasculitis - immunology
• ISSN: 0004-3591; 2326-5191; 1529-0131; 2326-5205
• DOI: 10.1002/art.38010

Objective Hypocomplementemic urticarial vasculitis syndrome (HUVS) is characterized by recurrent urticaria along with dermal vasculitis, arthritis, and glomerulonephritis. Systemic lupus erythematosus (SLE) develops in >50% of patients with HUVS, although the pathogenesis is unknown. The aim of this study was to identify the causative DNA mutations in 2 families with autosomal‐recessive HUVS, in order to reveal the pathogenesis and facilitate the laboratory diagnosis. Methods Autozygosity mapping was combined with whole‐exome sequencing. Results In a family with 3 affected children, we identified a homozygous frameshift mutation, c.289_290delAC, in DNASE1L3. We subsequently identified another homozygous DNASE1L3 mutation leading to exon skipping, c.320+4delAGTA, in an unrelated family. The detected mutations led to loss of function, via either nonsense‐mediated messenger RNA decay or abolished endonuclease activity, as demonstrated by a plasmid nicking assay. Conclusion These results show that HUVS is caused by mutations in DNASE1L3, encoding an endonuclease that previously has been associated with SLE.