Mutations in the NDUFS6 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.Complex I deficiency with autosomal recessive inheritance results from mutation in nuclear-encoded subunit genes, including NDUFV1, NDUFV2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFA2, NDUFA11, NDUFAF3, NDUFAF10, NDUFB3, NDUFB9, ACAD9, FOXRED1, and MTFMT.
^Emahazion T, Beskow A, Gyllensten U, Brookes AJ (Nov 1998). "Intron based radiation hybrid mapping of 15 complex I genes of the human electron transport chain". Cytogenetics and Cell Genetics82 (1-2): 115–9. doi:10.1159/000015082. PMID9763677.
^Kirby DM, Salemi R, Sugiana C, Ohtake A, Parry L, Bell KM et al. (Sep 2004). "NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency". The Journal of Clinical Investigation114 (6): 837–45. doi:10.1172/JCI20683. PMID15372108.
^McFarland R, Kirby DM, Fowler KJ, Ohtake A, Ryan MT, Amor DJ et al. (Jan 2004). "De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency". Annals of Neurology55 (1): 58–64. doi:10.1002/ana.10787. PMID14705112.
^Haack TB, Haberberger B, Frisch EM, Wieland T, Iuso A, Gorza M et al. (Apr 2012). "Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing". Journal of Medical Genetics49 (4): 277–83. doi:10.1136/jmedgenet-2012-100846. PMID22499348.
^Triepels RH, Van Den Heuvel LP, Trijbels JM, Smeitink JA (2001). "Respiratory chain complex I deficiency". American Journal of Medical Genetics106 (1): 37–45. doi:10.1002/ajmg.1397. PMID11579423.
^Robinson BH (May 1998). "Human complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect". Biochimica Et Biophysica Acta1364 (2): 271–86. PMID9593934.
Loeffen J, van den Heuvel L, Smeets R, Triepels R, Sengers R, Trijbels F et al. (Jun 1998). "cDNA sequence and chromosomal localization of the remaining three human nuclear encoded iron sulphur protein (IP) subunits of complex I: the human IP fraction is completed". Biochemical and Biophysical Research Communications247 (3): 751–8. doi:10.1006/bbrc.1998.8882. PMID9647766.
Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ et al. (Dec 1998). "cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed". Biochemical and Biophysical Research Communications253 (2): 415–22. doi:10.1006/bbrc.1998.9786. PMID9878551.
Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ et al. (Jun 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology22 (6): 707–16. doi:10.1038/nbt971. PMID15146197.