Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency. (November 2018)

• Record Type: Journal Article
• Authors: Srivastava, Anshika; Srivastava, Kinshuk; Hebbar, Malavika; Galada, Chelna; Kadavigrere, Rajagopal; Su, Fengyun; Cao, Xuhong; Chinnaiyan, Arul; Girisha, Katta; Shukla, Anju; Bielas, Stephanie
• Is Part Of: European journal of human genetics. Volume 26:Number 11(2018)
• Page Start: 1582
• Page End: 1587
• Publication Date: 2018-11
• Subjects: Human genetics -- Periodicals; Medical genetics -- Periodicals; 616.042
• DOI: 10.1038/s41431-018-0209-0
• Languages: English
• ISSNs: 1018-4813

Abstract

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 inNDUFV1 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.