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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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

Fingerprint

Population
Leigh Disease
Exome
Electron Transport Complex I
Flavin Mononucleotide
Brain Diseases
Muscular Diseases
Genomics
NAD
Biomedical Research
Mitochondrial complex I deficiency
Electrons

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Srivastava, A., Srivastava, K. R., Hebbar, M., Galada, C., Kadavigrere, R., Su, F., ... 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
Srivastava, Anshika ; Srivastava, Kinshuk Raj ; Hebbar, Malavika ; Galada, Chelna ; Kadavigrere, Rajagopal ; Su, Fengyun ; Cao, Xuhong ; Chinnaiyan, Arul M. ; Girisha, Katta M. ; Shukla, Anju ; Bielas, Stephanie L. / Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency. In: European Journal of Human Genetics. 2018 ; Vol. 26, No. 11. pp. 1582-1587.
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Srivastava, A, Srivastava, KR, Hebbar, M, Galada, C, Kadavigrere, R, Su, F, Cao, X, Chinnaiyan, AM, Girisha, KM, Shukla, A & Bielas, SL 2018, 'Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency', European Journal of Human Genetics, vol. 26, no. 11, pp. 1582-1587. https://doi.org/10.1038/s41431-018-0209-0

Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency. / Srivastava, Anshika; Srivastava, Kinshuk Raj; Hebbar, Malavika; Galada, Chelna; Kadavigrere, Rajagopal; Su, Fengyun; Cao, Xuhong; Chinnaiyan, Arul M.; Girisha, Katta M.; Shukla, Anju; Bielas, Stephanie L.

In: European Journal of Human Genetics, Vol. 26, No. 11, 01.11.2018, p. 1582-1587.

Research output: Contribution to journalArticle

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AU - Srivastava, Anshika

AU - Srivastava, Kinshuk Raj

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AU - Galada, Chelna

AU - Kadavigrere, Rajagopal

AU - Su, Fengyun

AU - Cao, Xuhong

AU - Chinnaiyan, Arul M.

AU - Girisha, Katta M.

AU - Shukla, Anju

AU - Bielas, Stephanie L.

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Srivastava A, Srivastava KR, Hebbar M, Galada C, Kadavigrere R, Su F et al. Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency. European Journal of Human Genetics. 2018 Nov 1;26(11):1582-1587. https://doi.org/10.1038/s41431-018-0209-0