Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

Lemaire et al. (2013)

Nature Genetics 45 (5): 531–536.

Atypical hemolytic-uremic syndrome (aHUS; MIM 615008) is a rare thrombotic disorder in the small vessels of the kidneys resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Compared to the typical form of the disease (HUS), which is triggered by bacterial toxins and generally treated to full recovery, aHUS is caused by genetic or autoimmune factors. The familial form of aHUS also has a poor clinical prognosis with approximately 60% of patients progressing to end-stage renal disease and a mortality rate of 25%. [1] To date, mutations in nine genes (CFH, CFHR1/3/4, MCP, CFI, CFB, C3, THBD) involved in the complement system cascade are known to be associated with aHUS. The disease primarily affects children, but the penetrance, severity, treatment and short-term and long-term outcomes of the disorder depend on the underlying genetic mutation.

Recently, Lemaire et al. (2013) reported recessive mutations in diacylglycerol kinase epsilon (DGKE) as a cause for a clinically specific form of aHUS, implicating a novel genetic cause that is unrelated to genes involved in the complement cascade pathway. The authors studied two sibling pairs from unrelated families who were diagnosed with aHUS at infancy but lacked mutations in known disease gene. Exome sequencing of the four affected patients, identified a rare homozygous DGKE variant (p.Trp322*) in kindred 1 and a shared compound heterozygous DGKE genotype (p.Val153Serfs*3, p.Arg64Pro) in kindred 2. Sequencing of an additional 47 unrelated probands with pediatric onset aHUS identified six more children carrying rare recessive mutations in DGKE. Furthermore, 22% of the siblings of index cases carried pathogenic mutations and linkage analysis of the families showed perfect co-segregation (LOD score of 8.9) of aHUS with the rare and highly penetrant DGKE variants. In total, 13 patients from 9 unrelated families with no abnormalities in the complement system genes were identified to have homozygous or compound heterozygous mutations in DGKE. In contrast, none of the 26 adult-onset probands examined were found to have recessive DGKE mutations.

The unique clinical features of DGKE-associated aHUS are of importance to the clinical genetics community. All affected patients with DGKE mutations presented aHUS before their first year of age (mean 0.5 years). Strikingly, DGKE carriers accounted for 50% of familial aHUS in the 1-year or younger age group of a large cohort containing patients of different aHUS subtypes. Considering that the age of onset guides genetic investigation, these findings may be of importance to clinical geneticists when screening for mutations in infants presenting aHUS-like symptoms. [2] Another unique feature seen in the DGKE-associated patients is the persistence of renal abnormalities between episodes, which is uncommon in other aHUS subtypes. Specifically, all but one patient suffered from chronic hypertension, microhematuria and proteinuria after renal function recovery. Furthermore, three patients eventually developed nephrotic syndrome, which is extremely rare in other forms of aHUS. Interestingly, two children treated with anti-complement therapy (eculizumab and plasma infusions, respectively) actually developed acute aHUS relapses. In addition, individuals who received renal transplants did not have any aHUS reoccurrences, which is very frequent in patients with aHUS caused by defects in the complement cascade.

DGKE is a lipid kinase involved in the regulation of diacylglycerols (DAGs) in the phosphatidylinositol (PI) pathway. This enzyme catalyzes the phosphorylation of arachinodonic acid-containing DAG (AADAG) to phosphatidic acid, effectively inhibiting the activation of AADAG-dependent protein kinase C (PKC). One of the downstream effects of PKC activation is the production of prothrombotic factors, such as Von Willebrand factor and plasminogen activator inhibitor, in endothelial cells. Thus, it is proposed that DGKE insufficiency leads to sustained AADAG signaling resulting in a prothrombotic state. Lemaire et al. demonstrate DGKE expression in endothelial cells and platelets, which are important cells involved in clotting. They also show DGKE staining in podocytes and endothelium of glomerular capillaries in a healthy human kidney. Further work is required to fully understand the mechanism behind DGKE deficiency and aHUS.

The findings of this study show a genetic defect in DGKE as a novel cause for a specific form of aHUS with unique clinical presentations. The involvement of DGKE in the complement cascade has yet to be identified, suggesting the possibility of an alternative or more complex disease-causing mechanism than previously thought. From this, immediate considerations should be made for current treatment options. Recommended therapies that target the complement cascade, such as eculizumab and C5 antibodies, will likely be ineffective in patients with DGKE mutations. Furthermore, the identification of the PI pathway and PKC signaling as components of the disease mechanism offers new therapeutic targets to be examined for the treatment of a clinically severe and penetrant form of aHUS.


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