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Kidney Week

Abstract: FR-PO810

Molecular Genetic Investigations Identify New Clinical Phenotypes Associated with BCSL1-Related Mitochondrial Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Author

  • Sayer, John Andrew, Newcastle University, Newcastle, United Kingdom
Introduction



The human BSC1L gene encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which has a known role in the assembly of Complex III of the mitochondrial respiratory chain. Several human disease phenotypes have been reported in association with pathogenic BCS1L variants, including severe presentations with Growth Retardation, Aminoaciduria, Chloestasis, Iron overload, Lactic acidosis and Early death (GRACILE syndrome) and the relatively mild Björnstad syndrome, characterised by abnormal flattening and twisting of hair shafts (pili torti) and hearing problems.

Case Description

Here we describe a patient who presented as an adult with aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties. He also exhibited progressive chronic kidney disease and is approaching end stage renal disease age 49 years. The diagnosis was not obvious. Whole genome sequencing revealled bi-allelic variants in BCS1L; the first with a previously reported c.166C>T, p.(Arg56*) heterozygous variant together with a novel pathogenic heterozygous variant c.205C>T, p.(Arg69Cys). Characterisation of cellular consequences of BCS1L variants confirmed a decrease in BCS1L protein levels. Biochemical analysis of Complex III revealed normal respiratory chain enzyme activities in the muscle but a decrease in Complex III assembly was detected in cultured fibroblasts.

Discussion

Together, these data support the pathogenicity of the novel BCS1L variants identified in our patient and emphasise the importance of consideration of a mitochondrial disease in unexplained CKD with multisystem features.