Various phenotypes of disease associated with mutated DGKE gene

Abstract

Atypical haemolytic uraemic syndrome and steroid-resistant nephrotic syndrome are highly rare kidney diseases that can occur in childhood. In some cases, genetic variants may trigger these conditions, although in atypical haemolytic uraemic syndrome they mostly confer only a predisposition to the disease. Most variants causing atypical haemolytic uraemic syndrome were identified in genes encoding proteins regulating the complement pathway; on the other hand, there are approximately 58 genes encoding distinct proteins primarily causing steroid-resistant nephrotic syndrome. We present a child with steroid-resistant nephrotic syndrome and a confirmed homozygous c.966G > A, p.Trp322Ter pathogenic variant in DGKE. This variant was also found in compound with a novel DGKE heterozygous deletion c.171delG, p.Ser58Alafs*111 in a patient from our paediatric cohort with atypical haemolytic uraemic syndrome. Both cases presented with hypertension, nephrotic proteinuria and severe acute kidney injury followed by renal recovery; however, their renal histology was different. In this paper, we deal with the clinical course of children with disrupted DGKE, including the steroid-resistant nephrotic syndrome and atypical haemolytic uraemic syndrome overlap.

Introduction

Atypical haemolytic uraemic syndrome (aHUS) is considered a two- or three-hit (or multifactorial) disease with manifestations of nonimmune haemolytic anaemia, thrombocytopenia and acute kidney injury (AKI). Genetic variants associated with aHUS account for approximately 60% of the cases and are mainly limited to the genes encoding factors that play roles in the alternative complement pathway (AP) regulation (Nester et al., 2015). Dysregulation of the AP by mutated pathway regulator genes (e.g. CFH, CFI, MCP) may lead to microthrombi formation and significant tissue damage, but gene variants are usually only one of the hits necessary for disease manifestation, not the direct cause of the disease (Nester et al., 2015; Noris et al., 2015).

The genetic steroid-resistant nephrotic syndrome (SRNS) is a subtype of the nephrotic syndrome characterised by non-response to corticosteroid therapy and causative variants (the only cause of the genetic SRNS) identified in one of the genes associated with podocyte damage. So far, more than 50 genes have been identified in connection with monogenic SRNS. Most cases are caused by causative variants in genes which encode structural components of the podocyte slit membrane or podocyte cytoskeleton, mitochondrial proteins, transcription factors, etc. (Rheault and Gbadegesin, 2016; Bierzynska et al., 2017).

Of note, both diseases may be caused by recessive pathogenic variants of the DGKE gene, which were first described in association with aHUS, but recently, there have been cases of DGKE nephropathy presenting as membranoproliferative glomerulonephritis (MPGN) or rarely as SRNS. According to the previous literature, it appears that pathogenic variants of DGKE are a direct cause of both aHUS and SRNS (Lemaire et al., 2013; Ozaltin et al., 2013; Sanchez Chinchilla et al., 2014; Westland et al., 2014; Azukaitis et al., 2017; Besbas et al., 2017; Bierzynska et al., 2017; Bezdicka et al., 2018). This gene encodes diacylglycerol kinase-epsilon (DGKε), an important intracellular enzyme likely involved in the regulation of arachidonic acid-containing diacylglycerol (AADAG) signalling (Ozaltin et al., 2013). The loss of DGKε function results in elevated AADAG signalling, which activates protein kinase c, which may induce a hypercoagulable state with platelet activation and thrombosis development. Elevated AADAG levels can also induce a protein kinase c-independent activation of podocyte calcium cation channels, leading to actin cytoskeletal rearrangements (Lemaire et al., 2013; Ozaltin et al., 2013; Quaggin, 2013; Noris et al., 2015). This paper describes the different disease courses of DGKE nephropathy in children from our Czech cohort, including the unique phenotype of SRNS/aHUS overlap.