A systematic review on the biochemical threshold of mitochondrial genetic variants

Table 6.

Complex V variants

Disease/clinical features Variant Subunit AA change Agea % VAF Complex V Reference
Muscle Blood Fibroblasts Other Residual activity, % Protein levels
Hypertrophic cardiomyopathy and neuropathy 8529G > A MT-ATP8 Trp55X 16 yr 90 90 100, cybrids 17, muscleb
21, fibroblastsb
16, cybridsb		 ↓ (Jonckheere et al. 2008)
MILS 8993T > C MT-ATP6 Leu156Pro 5 yr 94 94 98 81, fibroblasts (Santorelli et al. 1996)
NARP 8993T > C MT-ATP6 Leu156Pro 13 yr 94 94 98 86, fibroblasts (Santorelli et al. 1996)
Spinocerebellar ataxia/Leigh syndrome 8993T > C MT-ATP6 Leu156Pro 23 yr 94 94 98 32, fibroblasts (Santorelli et al. 1996)
MILS 8993T > C MT-ATP6 Leu156Pro 4 yr 94 94 98 10, fibroblasts (Santorelli et al. 1996)
Mitochondrial encephalomyopathy 8993T > C MT-ATP6 Leu156Pro >95 >95 41, muscle ↓ (Morava et al. 2006)
Mitochondrial encephalomyopathy 8993T > C MT-ATP6 Leu156Pro >95 >95 49, muscle ↓ (Morava et al. 2006)
Mitochondrial encephalomyopathy 8993T > C MT-ATP6 Leu156Pro >95 >95 52, muscle ↓ (Morava et al. 2006)
Mitochondrial encephalomyopathy 8993T > C MT-ATP6 Leu156Pro >95 >95 29, muscle ↓ (Morava et al. 2006)
Mitochondrial encephalomyopathy 8993T > C MT-ATP6 Leu156Pro >95 >95 25, muscle ↓ (Morava et al. 2006)
Leigh syndrome 8993T > G MT-ATP6 Leu156Arg 1 yr 94 92, lymphocytes 181, muscle (Tulinius et al. 1995)
Asymptomatic 8993T > G MT-ATP6 Leu156Arg 37 38, lymphocytes 521, muscle (Tulinius et al. 1995)
Leigh syndrome 8993T > G MT-ATP6 Leu156Arg >95, LCLs 35, LCLsb (Tatuch and Robinson 1993)
Leigh syndrome 8993T > G MT-ATP6 Leu156Arg >95, LCLs 54, LCLsb (Tatuch and Robinson 1993)
Leigh syndrome 8993T > G MT-ATP6 Leu156Arg >95, LCLs 34, LCLsb (Tatuch and Robinson 1993)
MILS 8993T > G MT-ATP6 Leu156Arg 100, cybrids 39, cybrids (Carrozzo et al. 2004b)
Leigh syndrome 8993T > G MT-ATP6 Leu156Arg <1 yr 95 95, brain
95, kidney
95, liver 		117, muscleb
78, fibroblastsb		 (Tatuch et al. 1992)
Muscle fatigue, headache, memory loss, paresthesias 8993T > G MT-ATP6 Leu156Arg 19 39 29, urinary epithelium
18, hair
10, platelets 		77, platelets (Carelli et al. 2002)
NARP syndrome 8993T > G MT-ATP6 Leu156Arg 91 92 91, urinary epithelium
95, hair
87, platelets 		4, plateletsb (Carelli et al. 2002)
NARP/Leigh syndrome 8993T > G MT-ATP6 Leu156Arg 85 86 88, urinary epithelium
78, hair
80, platelets 		9, plateletsb (Carelli et al. 2002)
Retinitis pigmentosa, ataxia 8993T > G MT-ATP6 Leu156Arg 55 34, platelets 30, plateletsb (Carelli et al. 2002)
NARP syndrome 8993T > G MT-ATP6 Leu156Arg 85 90, platelets 4, plateletsb (Carelli et al. 2002)
NARP/Leigh syndrome 8993T > G MT-ATP6 Leu156Arg 88 86 93, urinary epithelium
90, platelets 		7, platelets (Carelli et al. 2002)
Leigh syndrome 8993T > G MT-ATP6 Leu156Arg 91 75, cybrids Similar total levels of F1 as control cells but ↑ complex intermediates (García et al. 2000)
Leigh syndrome 8993T > G MT-ATP6 Leu156Arg 100 40, cybrids Similar total levels of F1 as control cells but ↑ complex intermediates (García et al. 2000)
Leigh syndrome 8993T > G MT-ATP6 Leu156Arg 96 79, cybrids (Bakare et al. 2021)
Developmental delay, abnormal gait 8993T > G MT-ATP6 Leu156Arg 91 38, cybrids (Bakare et al. 2021)
NARP/Leigh syndrome 8993T > G MT-ATP6 Leu156Arg <1 yr >95 >95 >95 42, muscle
33, fibroblasts
24, heart
28, brain 		(Uziel et al. 1997)
NARP/Leigh syndrome 8993T > G MT-ATP6 Leu156Arg >95 78, muscle
63, fibroblasts 		(Uziel et al. 1997)
NARP/Leigh syndrome 8993T > G MT-ATP6 Leu156Arg 85 >95 73 44, muscle
65, fibroblasts 		(Uziel et al. 1997)
NARP/Leigh syndrome 8993T > G MT-ATP6 Leu156Arg 66 81 59, fibroblasts (Uziel et al. 1997)
NARP/Leigh syndrome 8993T > G MT-ATP6 Leu156Arg 9 yr 83 83 83 71, muscle
51, fibroblasts 		(Uziel et al. 1997)
NARP/Leigh syndrome 8993T > G MT-ATP6 Leu156Arg 12 yr 87 58, muscle (Uziel et al. 1997)
Mitochondrial encephalomyopathy 8993T > G MT-ATP6 Leu156Arg >95 >95 27, muscle ↓ (Morava et al. 2006)
Mitochondrial encephalomyopathy 8993T > G MT-ATP6 Leu156Arg >95 >95 63, muscle ↓ (Morava et al. 2006)
Mitochondrial encephalomyopathy 8993T > G MT-ATP6 Leu156Arg >95 >95 50, muscle ↓ (Morava et al. 2006)
Mitochondrial encephalomyopathy 8993T > G MT-ATP6 Leu156Arg >95 >95 54, muscle ↓ (Morava et al. 2006)
Mitochondrial encephalomyopathy 8993T > G MT-ATP6 Leu156Arg >95 >95 40, muscle ↓ (Morava et al. 2006)
Mitochondrial encephalomyopathy 8993T > G MT-ATP6 Leu156Arg >95 >95 42, muscle ↓ (Morava et al. 2006)
NARP syndrome m.9127-9128 del AT MT-ATP6 Frameshift 18 yr 82 15 50 40, fibroblasts (Mordel et al. 2017)
Leigh syndrome 9176T > C MT-ATP6 Leu217Pro <1 yr >95 >95 100, fibroblasts (Dionisi-Vici et al. 1998)
Late onset spastic paraplegia-like disorder 9176T > C MT-ATP6 Leu217Pro 100 100 100 100, urinary sediment 126, fibroblasts ↓ Fully assembled complex V (Verny et al. 2011)
Late onset spastic paraplegia-like disorder 9176T > C MT-ATP6 Leu217Pro 100 100 100 100, urinary sediment 74, fibroblasts ↓ Fully assembled complex V (Verny et al. 2011)
Late onset spastic paraplegia-like disorder 9176T > C MT-ATP6 Leu217Pro 100 100 100 100, urinary sediment 95, fibroblasts ↓ Fully assembled complex V (Verny et al. 2011)
Late onset spastic paraplegia-like disorder 9176T > C MT-ATP6 Leu217Pro 100 100 100 100, urinary sediment 121, fibroblasts ↓ Fully assembled complex V (Verny et al. 2011)
Late onset spastic paraplegia-like disorder 9176T > C MT-ATP6 Leu217Pro 100 100 100 100, urinary sediment 97, fibroblasts ↓ Fully assembled complex V (Verny et al. 2011)
MILS 9176T > G MT-ATP6 Leu217Arg 100, cybrids 40, cybrids (Carrozzo et al. 2004b)
Leigh syndrome 9176T > G MT-ATP6 Leu217Arg 100 20, Fibroblasts (Carrozzo et al. 2004a)
Myopathy 9185T > C MT-ATP6 Leu220Pro 98 108, Fibroblasts (Bakare et al. 2021)

  • aAge of the patient at which the VAF and complex I activity were measured.

  • bNormalized to protein.

  • (AA) Amino acid; (VAF) variant allele frequency; (ATP) ATP synthase; (MILS) maternally inherited Leigh syndrome; (NARP) neuropathy, ataxia, and retinitis pigmentosa; and (LCLs) lymphoblastoid cell lines.

This Article

  1. Published in Advance April 16, 2024, doi: 10.1101/gr.278200.123 Genome Res. 34: 341-365

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