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Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autosomal recessive disorder marked by recurrent urticaria, dermal vasculitis, arthritis, and glomerulonephritis. Biallelic loss-of-function variants in DNASE1L3 underlie HUVS by impairing clearance of neutrophil extracellular traps and apoptotic debris, leading to complement activation and vasculitic inflammation ([PMID:23666765]).
Early genetic evidence emerged from two unrelated families: one sibship of three affected children homozygous for c.289_290delAC and a second family with a homozygous splice-site deletion c.320+4_320+7del, both resulting in nonsense-mediated decay or abolished endonuclease activity, confirmed by plasmid nicking assays ([PMID:23666765]).
A recent study of three Emirati families identified seven individuals with systemic lupus erythematosus and HUVS carrying homozygous c.572A>G (p.Asn191Ser) variants. Whole-exome and Sanger sequencing demonstrated autosomal recessive segregation, while HEK293 expression assays revealed markedly reduced DNASE1L3 secretion and enzymatic activity. A plasma NET assay showed significantly elevated NET burden in homozygotes (p=0.0409) relative to heterozygotes and controls, confirming pathogenicity of the missense allele ([PMID:39947743]).
Across all studies, at least ten probands from five unrelated families exhibit homozygous DNASE1L3 variants segregating with HUVS, and heterozygous carriers remain asymptomatic, supporting autosomal recessive inheritance. No founder alleles have been reported outside these cohorts.
The variant spectrum includes frameshift (c.289_290delAC), splice (c.320+4_320+7del), and missense (c.572A>G (p.Asn191Ser)) alleles, all demonstrating loss of nuclease function. Patients uniformly present with urticaria, vasculitis, arthritis, and glomerulonephritis, sometimes evolving into systemic lupus erythematosus.
Functional studies provide moderate evidence: endonuclease assays (plasmid nicking, NET degradation) and secretion analyses confirm loss-of-function mechanism with resultant NET accumulation and complement activation.
No studies to date dispute the DNASE1L3–HUVS association. Animal models for systemic sclerosis show dispensability of DNase1l3 but do not pertain to HUVS pathogenesis.
In summary, strong genetic and moderate functional evidence establish DNASE1L3 deficiency as a cause of HUVS. Genetic testing of DNASE1L3 in patients with early-onset HUVS guides diagnosis, genetic counseling, and potential interventions to mitigate NET-driven inflammation.
Key Take-home: Biallelic DNASE1L3 variants cause HUVS via loss of nuclease secretion and activity, leading to NET accumulation and complement-mediated vasculitis.
Gene–Disease AssociationStrong10 probands across five unrelated families, autosomal recessive segregation with loss-of-function alleles Genetic EvidenceStrongBiallelic frameshift, splice, and missense variants in 10 affected individuals from five families Functional EvidenceModerateHEK293 secretion and enzymatic assays plus NET burden studies demonstrate loss-of-function mechanism |