Abstract: SA-PO598
A Novel Deletion in ACTN4 in a Patient with Renal FSGS and Concomitant TMA
Session Information
- Noncystic Mendelian Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- Muench, Johannes, University Clinic Leipzig, Leipzig, Germany
- Wendt, Ralph, Hospital St. Georg , Leipzig, Germany
- Schönauer, Ria, University Clinic Leipzig, Leipzig, Germany
- Grohmann, Maik, Bioscientia, Ingelheim, Germany
- Beige, Joachim H., Hospital St. Georg , Leipzig, Germany
- Wiech, Thorsten, Department of Pathology, University Hospital Hamburg Eppendorf, Hamburg, Germany
- Lindner, Tom H., University Clinic Leipzig, Leipzig, Germany
- Bergmann, Carsten, Bioscientia, Ingelheim, Germany
- Halbritter, Jan, University Clinic Leipzig, Leipzig, Germany
Background
Thrombotic microangiopathy (TMA) of the kidney leading to renal failure is associated with genetic susceptibility due to variants of genes encoding complement components in the majority of cases. Recently, Challis et al (JASN 2016) reported two families with biopsy proven TMA who inherited mutations of INF2, a gene that is known to cause familial FSGS. As inverted formin 2 (INF2) is essential for podocytic cytoskeleton integrity by regulating the actin-polymerization and –depolymerization process, it is reasonable to assume, that genetically determined functional deficiency of further podocytic structural proteins might provoke renal TMA-phenotypes as well.
Methods
A 30-year old male patient presented with acute kidney failure and proteinuria (eGFR 11 ml/min, proteinuria 3563 mg/g creatinine). At the time of presentation, laboratory findings showed no signs of hemolytic anemia. Kidney biopsy revealed advanced glomerulosclerosis and TMA in preglomerular arterioles and glomeruli. Genetic testing regarding mutations of known aHUS-genes showed no pathogenic variants but the risk polymorphisms MCP-H2 and CFHR1*B. However, a novel heterozygous three-base deletion in exon 8 of ACTN4 was detected, leading to loss of lysine at amino acid residue 255 (c.763_765delAAG; p.Lys255del). A therapeutic approach with eculizumab was unsuccessful as control biopsy after four months revealed progressive glomerular and tubulointerstitial scarring.
Conclusion
ACTN4-mutations are known to cause autosomal dominant FSGS and most disease-causing mutations are located within the protein's actin-binding domain. The pathogenicity of the ACTN4 mutation in our patient is assumable, as functional alterations upon amino acid substitution at the same position (C.763A>G; p.Lys255Glu) have been demonstrated previously (Feng et al, PLoS One 2015). However, ACTN4 mutations have not been associated with renal TMA yet, although this phenotype was already reported in other forms of familial FSGS (Benz et al, Pediatr Nephrol 2007). We therefore propose that pathogenic variants in ACTN4 may account for renal TMA, which adds to the clinical pleiotropy of mutated ACTN4. Hence, mutated ACTN4 should be considered in patients with renal TMA, especially in those with an eculizumab-resistant progress and unremarkable complement genetics.
Funding
- Private Foundation Support