Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency

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.

Fig. 1

Brain imaging and NDUFV1 variants in Proband 1 and 2. a T1-weighted axial brain MRI of proband 1 at 6 months demonstrates pachy diffusion involving centrum semiovale, corona radiate (arrows), and periventricular external capsule (stars). Proband 2 T2 weighted axial brain MRI at 6 years of age shows diffuse white matter demyelination with gliotic areas and atrophy. b Pedigrees for family 1 and family 2, both of South Asian population. Filled symbols denote individuals affected with the MCID. Double lines denote consanguinity. c Sequence chromatograms showing the biallelic inheritance of NDUFV1 missense variants (black arrows) in proband 1 and 2 (lower panel, proband) consistent with consanguinity in the family

Fig. 2

a Schematic showing the intron-exon structure of human NDUFV1. The cDNA sequence from position 1111 (NM_007103.3) and the corresponding peptide sequence from Ile371 to Glu387 are shown. Genetic variants that affect function or amino acid substitutions identified in mitochondrial complex I deficiency patient are marked in red. b Structure of mammalian mitochondria and close-up depicting membrane embedded respiratory chain complexes. The circled region shows the N module of complex I, composed of NDUFV1, NDUFV2, and NDUFS1 proteins. Crystal structure of N module derived from T. thermophilus (3IAM), where colors denote distinct proteins (blue = NDUFV1, pink = NDUFS, and green = NDUFV2). Colored elements: Fe–S cluster = red and orange, FMN binding pocket = blue and green, and missense variants identified in proband 1 and 2 are encircled with bold circle. Dashed red lines denote the trajectory of shuttled electrons. c Magnified image of substituted amino acid close to FMN binding pocket in proband 1. The amino acid in black protruding out from alpha helix is the phenylalanine at position 373. The variation p.(Phe373Ser) disrupts the FMN binding to the NDUFV1. (d) Magnification of amino acids close to Fe–S cluster disrupted by proband 2 substitution. Arginine at position 386 is shown in red. The p.(Arg386Cys) substitution will alter buffering of Fe–S clusters and electrons transfer across NDUFV1