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Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. While complement dysregulation underlies most cases, recessive loss-of-function mutations in DGKE (diacylglycerol kinase ε) represent a distinct, complement-independent mechanism of aHUS. These mutations disrupt lipid signaling in endothelial cells, predisposing to a prothrombotic state and small vessel thrombosis. DGKE-associated aHUS typically presents in infancy or early childhood, though adult cases have been reported.
Genetic evidence supports an autosomal recessive inheritance pattern with extensive segregation. Over 25 unrelated aHUS patients with biallelic DGKE mutations have been documented across at least six cohorts, including consanguineous families and multi-patient registries ([PMID:23619787]). Segregation analysis in multiple families identified affected siblings carrying identical homozygous or compound heterozygous variants, with at least 7 additional affected relatives beyond index cases. Case series describe a spectrum of null and missense alleles—truncating variants (e.g., c.966G>A (p.Trp322Ter)), frameshifts (e.g., c.171del (p.Ser58AlafsTer111)), and missense substitutions in the catalytic and regulatory domains.
A representative recurrent variant is c.942C>G (p.Asn314Lys), identified homozygously in a 19-year-old female with early-onset aHUS and confirmed by Sanger sequencing and in silico modeling as damaging to protein stability ([PMID:32838746]). This allele segregated with disease in her family and is illustrative of the missense spectrum in DGKE. Functional null alleles have also been observed in registry studies, with DGKE mutations detected in 4 of 83 Spanish infantile aHUS patients and in 1 of 10 Taiwanese pediatric cases.
Functional studies reveal that DGKE loss-of-function leads to accumulation of diacylglycerol species that potentiate platelet activation and endothelial injury. In vitro assays using NBD-SAG substrate demonstrate that disruption of the C1B domain zinc finger (e.g., Cys135Ala, His161Ala) abrogates kinase activity and triggers proteasomal degradation, consistent with the recessive pathogenic mechanism ([PMID:36113832]). Animal and cellular models recapitulate the prothrombotic phenotype and support a therapeutic role for plasma infusion.
Treatment with eculizumab, the anti-complement C5 antibody, yields variable responses in DGKE-aHUS, reflecting the complement-independent pathogenesis; however, early plasma therapy has been shown to control systemic symptoms and preserve renal function in several cases ([PMID:24511134]). Long-term management strategies remain under investigation, with emphasis on prompt genetic diagnosis to guide complement blockade decisions and plasma-based interventions.
In summary, DGKE mutations constitute a definitive cause of recessive aHUS, with robust genetic segregation and mechanistic concordance. Genetic screening for DGKE should be included in diagnostic panels for infantile aHUS, as early identification enables tailored therapy. Key take-home: DGKE-associated aHUS is a distinct complement-independent variant amenable to early plasma therapy, underscoring the importance of rapid molecular diagnosis.
Gene–Disease AssociationDefinitiveOver 20 unrelated patients and multi-family segregation with concordant functional studies Genetic EvidenceStrongOver 25 recessive cases across multiple cohorts ([PMID:23619787]) Functional EvidenceModerateZinc finger motif disruption and in vitro assays demonstrate loss-of-function and prothrombotic state consistent with recessive mechanism ([PMID:36113832]) |