Novel MT-ND Gene Variants Causing Adult-Onset Mitochondrial Disease and Isolated Complex I Deficiency.

Yi Shiau Ng,Sandip Shaunak,Andrew M Schaefer,Kyle Thompson,Mark E Roberts,Daniela Loher,Steven A Hardy,James B Lilleker,Robert W Taylor,Sila Hopton,Gavin Falkous

doi:10.3389/fgene.2020.00024

Abstract

Mitochondrial complex I deficiency is associated with a diverse range of clinical phenotypes and can arise due to either mitochondrial DNA (mtDNA) or nuclear gene defects. We investigated two adult patients who exhibited non-syndromic neurological features and evidence of isolated mitochondrial complex I deficiency in skeletal muscle biopsies. The first presented with indolent myopathy, progressive since age 17, while the second developed deafness around age 20 and other relapsing-remitting neurological symptoms since. A novel, likely de novo, frameshift variant in MT-ND6 (m.14512_14513del) and a novel maternally-inherited transversion mutation in MT-ND1 were identified, respectively. Skewed tissue segregation of mutant heteroplasmy level was observed; the mutant heteroplasmy levels of both variants were greater than 70% in muscle homogenate, however, in blood the MT-ND6 variant was undetectable while the mutant heteroplasmy level of the MT-ND1 variant was low (12%). Assessment of complex I assembly by Blue-Native PAGE demonstrated a decrease in fully assembled complex I in the muscle of both cases. SDS-PAGE and immunoblotting showed decreased levels of mtDNA-encoded ND1 and several nuclear encoded complex I subunits in both cases, consistent with functional pathogenic consequences of the identified variants. Pathogenicity of the m.14512_14513del was further corroborated by single-fiber segregation studies.

Highlights

Mitochondrial NADH:ubiquinone oxidoreductase (Complex I) is the first and largest (~1 MDa) complex of the mitochondrial respiratory chain involved in the oxidative phosphorylation (OXPHOS) pathway and generation of ATP
While incomplete penetrance is frequently observed in the homoplasmic variants associated with Leber hereditary optic neuropathy (LHON), (Man et al, 2002) the heteroplasmy levels in other pathogenic variants such as m.13513G > A and m.13094T > C in MT-ND5, both reported in Leigh Syndrome and MELAS syndrome, show good correlation with the severity of disease burden (Ng et al, 2018)
We present two adult patients with complex I deficiency manifesting with different clinical pictures, one developing an insidious-onset myopathy while the other presents with deafness in her 20s and subsequent neurological symptoms that follow a relapsing-remitting pattern

Summary

Introduction

Mitochondrial NADH:ubiquinone oxidoreductase (Complex I) is the first and largest (~1 MDa) complex of the mitochondrial respiratory chain involved in the oxidative phosphorylation (OXPHOS) pathway and generation of ATP. It comprises 45 structural subunits of which seven are encoded by mitochondrial DNA (mtDNA), the remaining subunits being encoded by the mtDNA Mutations and Non-Syndromic Presentation nuclear genome as are the ~20 ancillary proteins required for assembly and biogenesis (Formosa et al, 2018). Some de novo pathogenic variants in the MT-ND (Mitochondrially-encoded NADH:ubiquinone oxidoreductase core subunit) genes cause slowly progressive, non-syndromic presentations such as myopathy and exercise intolerance (Gorman et al, 2015)

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