TTC19 – Leigh Syndrome

TTC19 encodes a tetratricopeptide repeat domain protein required for mitochondrial respiratory chain complex III (CIII) assembly. Biallelic loss-of-function variants in TTC19 cause an autosomal recessive form of Leigh syndrome, characterized by developmental regression, basal ganglia lesions on MRI, and progressive neurodegeneration. This summary integrates case series, segregation data, cellular assays, and animal models to support diagnostic decision-making and future research.

Multiple unrelated patients (12 probands [PMID:25899669]) have been reported with autosomal recessive TTC19-related CIII deficiency. Affected individuals present in infancy or childhood with global developmental delay, language regression, and Leigh-like MRI features involving the putamen, caudate, and brainstem (HP:0001263).

Segregation analysis in consanguineous families confirms recessive inheritance; homozygous and compound heterozygous TTC19 variants segregate with disease, with parents and unaffected siblings carrying single alleles ([PMID:25452764]). No dominant phenotypes or incomplete penetrance have been observed.

The variant spectrum is dominated by truncating and splice-site mutations predicted to abolish TTC19 protein. A representative allele is c.964_967delGGCT (p.Gly322MetfsTer8) ([PMID:24368687]), which causes frameshift and premature termination via nonsense-mediated decay.

Functional studies in patient fibroblasts demonstrate absent TTC19 protein, accumulation of CIII assembly intermediates on Blue Native PAGE, and impaired respiratory activity ([PMID:25452764]; [PMID:25772319]). Complementation restores CIII stability, confirming loss-of-function as the pathogenic mechanism.

A Ttc19?/? mouse model recapitulates progressive neurological decline, elevated reactive oxygen species, and reduced CIII enzymatic activity, providing in vivo evidence of TTC19’s role in mitochondrial function ([PMID:28673544]).

Together, the genetic and experimental data establish a strong clinical validity for TTC19 in autosomal recessive Leigh syndrome. TTC19 testing is recommended for patients with unexplained CIII deficiency or Leigh-like neuroimaging. Key take-home: Biallelic TTC19 loss-of-function variants produce a clinically recognizable mitochondrial Leigh syndrome via CIII assembly failure.

References

• JIMD Reports • 2014 • Mutations in the Complex III Assembly Factor Tetratricopeptide 19 Gene TTC19 Are a Rare Cause of Leigh Syndrome. PMID:24368687
• Frontiers in Genetics • 2014 • A novel mutation in TTC19 associated with isolated complex III deficiency, cerebellar hypoplasia, and bilateral basal ganglia lesions. PMID:25452764
• JIMD Reports • 2015 • Mitochondrial Complex III Deficiency Caused by TTC19 Defects: Report of a Novel Mutation and Review of Literature. PMID:25772319
• 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
• Molecular Cell • 2017 • TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III. PMID:28673544
• CNS Neuroscience & Therapeutics • 2024 • A TTC19 mutation associated with progressive movement disorders and peripheral neuropathy: Case report and systematic review. PMID:37927170

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