Compound heterozygosity for severe and hypomorphicNDUFS2mutations cause non-syndromic LHON-like optic neuropathy

Abstract

BackgroundNon-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non-consanguineous parents of French origin.MethodsWe used a combination of genetic analysis (gene mapping and whole-exome sequencing) in a multiplex family of non-syndromic HON and of functional analyses in patient-derived cultured skin fibroblasts and the yeast Yarrowia lipolytica.ResultsWe identified compound heterozygote NDUFS2 disease-causing mutations (p.Tyr53Cys; p.Tyr308Cys). Studies using patient-derived cultured skin fibroblasts revealed mildly decreased NDUFS2 and complex I abundance but apparently normal respiratory chain activity. In the yeast Y. lipolytica ortholog NUCM, the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively.ConclusionsBiallelism for NDUFS2 mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause non-syndromic HON. This observation suggests a direct correlation between the severity of NDUFS2 mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function.

Pathogenic mutations in NUBPL affect complex I activity and cold tolerance in the yeast model Yarrowia lipolytica

“…In summary, of the five NUBPL missense variants that were functionally assessed in Y. lipolytica , four (L104P, D105Y, L193F and G285C) were found to be deleterious to complex I and one (G138D) was found to exhibit a mild defect. Along with other studies ( 18 , 21 , 35 , 36 ), these results reconfirm the utility of Y. lipolytica as a model for human mitochondrial disorders. However, care must be taken in over-interpreting the results, as some effects seen in Y. lipolytica have not been found in humans.…”

Pathogenic mutations inNUBPLaffect complex I activity and cold tolerance in the yeast modelYarrowia lipolytica

“…In summary four of the six mutations (L104P, D105Y, L193F and G285C) were classed as pathogenic and one (G138D) was classed as potentially pathogenic. Along with other studies (17,20,33,34) these results reconfirm the utility of Y. lipolytica as a model for human mitochondrial disorders. However, care must be taken in over-interpreting the results as some effects seen in Y. lipolytica have not been found in humans.…”

Drug repurposing for mitochondrial diseases using a pharmacological model of complex I deficiency in the yeastYarrowia lipolytica

“…Yarrowia lipolytica has an ortholog of NDUFA8; truncation mutants are, as expected, inviable (Dr Mark Blenner, personal communication). As has been done for another nuclear encoded assembly factor gene in Yarrowia lipolytica (Gerber et al, 2017), hypomorphic NDUFA8 missense mutants are being generated now in collaboration with a lab at Clemson University so that the piericidin A suppressors described herein will be tested for their ability to rescue the growth defects of this mutant. Once validated in yeast and patient derived cells (fibroblasts, followed by iPSCs), piericidin A suppressors can be further validated in complex I deficient worms (Polyak et al, 2018), flies (Cabirol-Pol et al, 2018) and zebrafish (Pinho et al, 2013).…”