DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN

Özaltın, Fatih; Li, Binghua; Rauhauser, Alysha; An, Sung Wan; Söylemezoğlu, Oğuz; Gönül, İpek Işık; Taşkıran, Ekim Z.; Ibsirlioglu, Tulin; Korkmaz, Emine; Bilginer, Yelda; Düzova, Ali; Özen, Seza; Topaloğlu, Rezan; Beşbaş, Nesrin; Ashraf, Shazia; Du, Yong; Liang, Chao; Chen, Phylip; Lu, Dongmei; Vadnagara, Komal; Arbuckle, Susan; Lewis, Deborah L.; Wakeland, Benjamin; Quigg, Richard J.; Ransom, Richard F.; Wakeland, Edward K.; Topham, Matthew K.; Bazán, Nicolás G.; Mohan, Chandra; Hildebrandt, Friedhelm; Bakkaloğlu, Ayşı̇n; Huang, Chou Long; Attanasio, Massimo

doi:10.1681/asn.2012090903

Cited by 131 publications

(103 citation statements)

References 27 publications

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“…DGKE mutations accounted for 27% of HUS cases in the first year of life and 50% of familial forms in this age group. Three patients developed nephrotic syndrome within 3 to 5 years of diagnosis (33). Renal biopsies showed chronic TMA, a membranoproliferative pattern, and podocyte foot process effacement, consistent with nephrotic syndrome.…”

Section: Pathogenesis Of Ahusmentioning

confidence: 82%

See 1 more Smart Citation

Current treatment of atypical hemolytic uremic syndrome

Kaplan

Ruebner

Spinale

et al. 2014

IRDR

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Section: Pathogenesis Of Ahusmentioning

confidence: 82%

“…Diacylglycerol kinase ε (DGKE) and HUS: Recessive loss-of-function mutations in the gene DGKE can cause HUS (21,33,34) not associated with activation of alternate complement pathway activation. Recessive mutations in DGKE were detected by exome sequencing in nine unrelated kindreds (21).…”

Section: Pathogenesis Of Ahusmentioning

confidence: 99%

Current treatment of atypical hemolytic uremic syndrome

Kaplan

Ruebner

Spinale

et al. 2014

IRDR

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“…DGKE is expressed in peripheral blood leukocytes (23). To assess the effects of the c.888+40A.G mutation at a transcriptional level, we obtained peripheral blood samples from the siblings and parents from family 1 and from a healthy unrelated Italian control.…”

Section: Characterization Of the Effects Of C888+40a>g On Dgke Transmentioning

confidence: 99%

“…Exon 5 encodes part of the catalytic domain of DGKE ( Figure 4A) (23). Structural tridimensional modeling suggests that the 13 amino acid insertion in isoform 1 should result in structural changes that may affect DGKE kinase activity (Supplemental Figure 3 and Supplemental Material).…”

Section: Characterization Of the Effects Of C888+40a>g On Dgke Transmentioning

confidence: 99%

Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome

Mele¹,

Lemaire²,

Iatropoulos³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown.Design, setting, participants, & measurements Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS. Sequencing of cDNA from affected individuals was used to test for the presence of aberrant mRNA species. Expression of mutant diacylglycerol kinase epsilon (DGKE) protein was evaluated with western blotting.Results Whole-exome sequencing analysis with conventional variant filtering parameters did not reveal any obvious candidate mutation in the first family. The report of aHUS-associated mutations in DGKE, encoding DGKE, led to re-examination of the noncoding DGKE variants obtained from next-generation sequencing, allowing identification of a novel intronic DGKE mutation (c.888+40A.G) that segregated with disease. Sequencing of cDNA from affected individuals revealed aberrant forms of DGKE mRNA predicted to cause profound abnormalities in the protein catalytic site. By whole-genome sequencing, the same mutation was found in compound heterozygosity with a second nonsense DGKE mutation in all affected siblings of another unrelated family. Homozygous and compound heterozygous patients presented similar clinical features, including aHUS presentation in the first year of life, multiple relapsing episodes, and proteinuria, which are prototypical of DGKE-associated aHUS.Conclusions This is the first report of a mutation located beyond the exon-intron boundaries in aHUS. Intronic mutations such as these are underreported because conventional filtering parameters used to process nextgeneration sequencing data routinely exclude these regions from downstream analyses in both research and clinical settings. The results suggest that analysis of noncoding regions of aHUS-associated genes coupled with mRNA sequencing might provide a tool to explain genetically unsolved aHUS cases.

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“…Recently, mutations in diacylglycerol kinase ε (DGKE) have been found to cause HUS-like disease. Currently, it has only been described in paediatric patients younger than 1 year [20] and has also been associated with a membranoproliferative glomerulonephritis (MPGN)-like syndrome in nine patients from three families [21]. Some of these patients with mutations in DGKE have been found to carry additional mutations in complement genes, and therefore the involvement of complement dysregulation in patients with DGKE mutations remains unclear [18].…”

Section: Atypical Haemolytic Uraemic Syndromementioning

confidence: 99%

Atypical hemolytic uremic syndrome: from diagnosis to treatment

Franchini¹

2015

Clinical Chemistry and Laboratory Medicine (CCLM)

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Thrombotic microangiopathy (TMA) is a relatively rare condition but a medical urgency requiring immediate intervention to avoid irreversible organ damage or death. Symptoms on presentation include microangiopathic haemolytic anaemia, thrombocytopenia and organ damage. The most frequent direct causes of TMA are thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome (HUS). The most common form of HUS is related to Shiga toxin producing Escherichia coli (STEC) infection while approximately 10% of cases are due to dysregulation of the complement pathway (atypical haemolytic uremic syndrome, aHUS). Optimal treatment regimens differ depending on the underlying cause; however, differential diagnosis may be difficult. The most accurate method of diagnosis is based on exclusion and should consider, beyond the symptoms common to TMA, ADAMTS13 activity levels and STEC infection status. For the management of TTP, plasma exchange (PE) is the most important acute intervention and is associated with lower mortality and better outcomes than plasma infusion. In most patients with STEC-HUS, the course of disease is selflimiting although management of acute kidney injury is often required. Until recently, the management of aHUS consisted of early and intensive PE, although this was mostly ineffective in protecting from subsequent organ damage. Eculizumab, an inhibitor of the alternative complement pathway, produces a rapid and sustained inhibition of the TMA process, with significant improvements in long-term clinical outcomes. Due to the significant improvement achieved, eculizumab has subsequently been approved as first-line therapy when an unequivocal diagnosis of aHUS has been made.

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DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN

Cited by 131 publications

References 27 publications

Current treatment of atypical hemolytic uremic syndrome

Current treatment of atypical hemolytic uremic syndrome

Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome: from diagnosis to treatment

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