TTC19 and Mitochondrial Complex III Deficiency

TTC19 encodes a mitochondrial inner-membrane tetratricopeptide repeat protein essential for assembly and stability of respiratory chain complex III. Bi-allelic loss-of-function variants in TTC19 result in autosomal recessive mitochondrial complex III deficiency, presenting with early neurodegeneration, ataxia and spasticity. Patients often exhibit cerebellar hypoplasia, basal ganglia lesions and progressive motor decline, underscoring the critical role of TTC19 in oxidative phosphorylation.

Multiple case reports describe homozygous frameshift or nonsense TTC19 variants in patients with isolated complex III deficiency. A novel c.213_229dup (p.Gln77ArgfsTer30) was identified in a 9-year-old girl with unsteady gait and tetraparesis ([PMID:25452764]). An Iraqi child carried a homozygous c.937C>T (p.Gln313Ter) with failure to thrive and Leigh-like MRI changes ([PMID:25899669]). A Japanese adult harbored c.157_158dup (p.Pro54AlafsTer48), presenting with spastic paraparesis and ataxia ([PMID:25652355]). A Chinese boy was reported with c.719-732del (p.Leu240SerfsTer17) and progressive movement disorder ([PMID:37927170]).

To date, 11 probands ([PMID:25899669]) from at least six unrelated families have been described, all with autosomal recessive inheritance and bi-allelic loss-of-function TTC19 alleles. No additional affected relatives with confirmed segregation have been reported. The variant spectrum is dominated by frameshift and nonsense changes; no recurrent founder alleles have been established.

Functional assays demonstrate absence of TTC19 protein in patient fibroblasts and accumulation of cIII assembly intermediates on Blue-Native PAGE ([PMID:25452764]). A Ttc19 knockout mouse model recapitulates progressive neurological decline, decreased complex III enzymatic activity and increased reactive oxygen species ([PMID:28673544]), confirming the pathogenic mechanism.

Mechanistically, TTC19 is required for removal of immature UQCRFS1 fragments during holocomplex III maturation; its loss leads to stalled assembly intermediates and impaired electron transport. These findings support a haploinsufficiency mechanism driven by complete loss of TTC19 function.

Overall, the convergence of robust genetic evidence and concordant functional data justifies a Strong ClinGen classification for the TTC19–mitochondrial complex III deficiency association. TTC19 sequencing should be incorporated into diagnostic panels for patients with unexplained complex III deficiency. Key take-home: Biallelic TTC19 loss-of-function variants cause autosomal recessive mitochondrial complex III deficiency with prominent neurodegenerative features.

References

• Frontiers in genetics • 2014 • A novel mutation in TTC19 associated with isolated complex III deficiency, cerebellar hypoplasia, and bilateral basal ganglia lesions PMID:25452764
• American journal of medical genetics. Part A • 2015 • Phenotypic variation of TTC19-deficient mitochondrial complex III deficiency: a case report and literature review PMID:25899669
• Journal of human genetics • 2015 • A Japanese case of cerebellar ataxia, spastic paraparesis and deep sensory impairment associated with a novel homozygous TTC19 mutation PMID:25652355
• CNS neuroscience & therapeutics • 2024 • A TTC19 mutation associated with progressive movement disorders and peripheral neuropathy: Case report and systematic review PMID:37927170
• Molecular cell • 2017 • TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III PMID:28673544

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