The T616C tRNA(Phe) mutation causes mitochondrially inherited tubulointerstitial kidney disease

Abstract

Aim: To identify the genetic cause of genetic renal disease (GRD) in a large Australian family whose pedigree is consistent with autosomal dominant or mitochondrial inheritance. Background: Mutations in tRNA(Phe) are rarely reported to cause renal disease, usually with syndromic features such as epilepsy and myopathy. Methods: A large Australian family with GRD underwent whole exomic sequencing (WES) with mtGenome capture, and mtDNA sequencing. Results: The family has extensive kidney disease historically identified as “Medullary Cystic Kidney Disease”. Six surviving members receive renal replacement therapy or have a functioning renal transplant. Seven further deceased family members had Chronic or End-Stage Kidney Disease. No clear history of an extrarenal phenotype is apparent, though one affected family member has an undiagnosed oromotor dysphagia parkinsonian syndrome and another died of apparent herpetic encephalitis. Renal histopathology in three affected family members >30 years ago demonstrated tubulointerstitial disease with mild tubular dilatation and some corticomedullary cyst formation. WES did not reveal any candidate variants in the nuclear genome. mtDNA sequencing identified the T616C mutation in the anticodon loop of tRNA(Phe). This mutation was homoplasmic in blood and present in all affected family members including 4th degree cousins. Northern blot demonstrated decreased phenylalanine tRNA in affected fibroblasts compared to wild-type control fibroblasts. A respiratory chain defect was present in affected fibroblasts and cybrids compared to wild-type, confirming the mitochondrial origin. Conclusions: Here we confirm the T616C tRNA(Phe) mutation as causative for Mitochondrially Inherited Tubulointerstitial Kidney Disease, in the apparent absence of extrarenal syndromic features. This has implications for genetic counselling and demonstrates the utility of collaborative genetic diagnostic approaches. The pathobiology of how such mitochondrial mutations cause renal disease requires further research.L719958762015-09-08 <br />