TTC19 – Mitochondrial Complex III Deficiency Nuclear Type 2

TTC19 encodes a tetratricopeptide repeat–containing assembly factor critical for mitochondrial complex III stability and electron transfer. Biallelic loss-of-function variants in TTC19 define mitochondrial complex III deficiency nuclear type 2, an autosomal-recessive disorder of impaired coenzyme Q–cytochrome C oxidation and ATP synthesis. Multiple independent reports have established a consistent genotype–phenotype correlation.

At least six unrelated probands have been described with homozygous TTC19 LoF variants in consanguineous pedigrees ([PMID:31551910]). These cases satisfy diagnostic criteria for nuclear type 2 complex III deficiency, with no evidence of dominant-negative effects or phenotypic heterogeneity outside the core syndrome.

Reported variants are predominantly frameshift (n = 5) and essential splice-site (n = 1) alleles predicted to truncate or abolish TTC19. The c.581delG (p.Arg194AsnfsTer16) variant was identified in a 15-year-old boy with psychiatric manifestations, progressive cerebellar ataxia, spastic paraparesis, basal ganglia involvement, cerebellar atrophy, and later gastrointestinal dysmotility ([PMID:31551910]). Other recurrent alleles include c.213_229dup (p.Gln77ArgfsTer30) ([PMID:25452764]), c.782_786delinsGAAAAG (p.Glu261GlyfsTer6) ([PMID:25772319]), and c.157_158dup (p.Pro54AlafsTer48) ([PMID:25652355]).

Clinically, affected individuals present with progressive cerebellar ataxia and spastic paraparesis, often accompanied by cognitive decline, psychiatric features, and MRI findings of cerebellar atrophy with basal ganglia lesions. Gastrointestinal involvement has been newly recognized, expanding the phenotypic spectrum ([PMID:31551910]). Leigh-like brain lesions and retinal cherry-red spots have also been documented in earlier reports ([PMID:25899669]).

Functional assays in patient fibroblasts demonstrate absence of TTC19 protein and accumulation of complex III assembly intermediates by blue-native PAGE ([PMID:25452764]; [PMID:25772319]). A Ttc19−/− mouse model recapitulates progressive neurologic decline, reduced complex III activity, and increased reactive oxygen species, supporting a loss-of-function mechanism underlying haploinsufficiency ([PMID:28673544]).

No conflicting evidence has been reported. The convergence of genetic and experimental data supports a strong gene–disease relationship for TTC19 and mitochondrial complex III deficiency nuclear type 2. Key take-home: TTC19 sequencing is clinically useful for diagnosis of unexplained autosomal-recessive cerebellar ataxia with complex III biochemical defects.

References

• Frontiers in neurology • 2019 • A Novel TTC19 Mutation in a Patient With Neurological, Psychological, and Gastrointestinal Impairment. PMID:31551910
• 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
• 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
• 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
• 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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