Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency.
Eur J Hum Genet
; 26(11): 1582-1587, 2018 11.
Article
em En
| MEDLINE
| ID: mdl-29976978
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Mutação de Sentido Incorreto
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Doenças Mitocondriais
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Complexo I de Transporte de Elétrons
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NADH Desidrogenase
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Child
/
Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Eur J Hum Genet
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos