%A Ng,Yi Shiau %A Thompson,Kyle %A Loher,Daniela %A Hopton,Sila %A Falkous,Gavin %A Hardy,Steven A. %A Schaefer,Andrew M. %A Shaunak,Sandip %A Roberts,Mark E. %A Lilleker,James B. %A Taylor,Robert W. %D 2020 %J Frontiers in Genetics %C %F %G English %K mitochondrial DNA,Tissue segregation,Deafness,Myopathy,Muscle biopsy %Q %R 10.3389/fgene.2020.00024 %W %L %M %P %7 %8 2020-February-25 %9 Brief Research Report %+ Prof Robert W. Taylor,Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University,United Kingdom,robert.taylor@ncl.ac.uk %+ Prof Robert W. Taylor,Newcastle upon Tyne Hospitals NHS Foundation Trust, NHS Highly Specialised Service for Rare Mitochondrial Disorders,United Kingdom,robert.taylor@ncl.ac.uk %# %! mtDNA mutations and non-syndromic presentation %* %< %T Novel MT-ND Gene Variants Causing Adult-Onset Mitochondrial Disease and Isolated Complex I Deficiency %U https://www.frontiersin.org/articles/10.3389/fgene.2020.00024 %V 11 %0 JOURNAL ARTICLE %@ 1664-8021 %X 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.