Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency

Anshika Srivastava, Kinshuk Raj Srivastava, Malavika Hebbar, Chelna Galada, Rajagopal Kadavigrere, Fengyun Su, Xuhong Cao, Arul M. Chinnaiyan, Katta M. Girisha, Anju Shukla, Stephanie L. Bielas

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Abstract

Medical genomics research performed in diverse population facilitates a better understanding of the genetic basis of developmental disorders, with regional implications for community genetics. Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for a constellation of clinical features, including encephalopathies, myopathies, and Leigh Syndrome. Using whole-exome sequencing, we identified biallelic missense variants in NDUFV1 that encodes the 51-kD subunit of complex I (NADH dehydrogenase) NDUFV1. Mapping the variants on published crystal structures of mitochondrial complex I demonstrate that the novel c.1118T > C (p.(Phe373Ser)) variant is predicted to diminish the affinity of the active pocket of NDUFV1 for FMN that correlates to an early onset of debilitating MCID symptoms. The c.1156C > T (p.(Arg386Cys)) variant is predicted to alter electron shuttling required for energy production and correlate to a disease onset in childhood. NDUFV1 c.1156C > T (p.(Arg386Cys)) represents a founder variant in South Asian populations that have value in prioritizing this variant in a population-specific manner for genetic diagnostic evaluation. In conclusion, our results demonstrate the advantage of analyzing population-specific sequences to understand the disease pathophysiology and prevalence of inherited risk variants in the underrepresented populations.

Original languageEnglish
Pages (from-to)1582-1587
Number of pages6
JournalEuropean Journal of Human Genetics
Volume26
Issue number11
DOIs
Publication statusPublished - 01-11-2018

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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    Srivastava, A., Srivastava, K. R., Hebbar, M., Galada, C., Kadavigrere, R., Su, F., Cao, X., Chinnaiyan, A. M., Girisha, K. M., Shukla, A., & Bielas, S. L. (2018). Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency. European Journal of Human Genetics, 26(11), 1582-1587. https://doi.org/10.1038/s41431-018-0209-0