A Japanese case of cerebellar ataxia, spastic paraparesis and deep sensory impairment associated with a novel homozygous TTC19 mutation

Kunii, Misako; Doi, Hiroshi; Higashiyama, Yuichi; Kugimoto, Chiharu; Ueda, Naohisa; Hirata, Junichi; Katsumoto, Atsuko; Kashikura-Kojima, Mari; Kubota, Shohei; Taniguchi, Masaharu; Murayama, Kei; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Miyake, Noriko; Saitsu, Hirotomo; Matsumoto, Naomichi; Tanaka, Fumiaki

doi:10.1038/jhg.2015.7

Cited by 14 publications

(15 citation statements)

References 27 publications

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“…Loss-of-function mutations in TTC19 have been found in patients with cIII 2 deficiency associated with heterogeneous neurological syndromes (Ardissone et al, 2015;Atwal, 2014;Ghezzi et al, 2011;Kunii et al, 2015;Melchionda et al, 2014;Mordaunt et al, 2015;Morino et al, 2014;Nogueira et al, 2013). TTC19 ablation in D. melanogaster causes cIII 2 deficiency associated with a neurological phenotype in adult flies (Ghezzi et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Pathogenic mutations have been found in some of cIII 2 -related ancillary factors, including BCS1L (de Lonlay et al, 2001;Fellman, 2002;Fernandez-Vizarra et al, 2007;Hinson et al, 2007;Morá n et al, 2010;Ramos-Arroyo et al, 2009), TTC19 (Ardissone et al, 2015;Atwal, 2014;Ghezzi et al, 2011;Kunii et al, 2015;Melchionda et al, 2014;Mordaunt et al, 2015;Morino et al, 2014;Nogueira et al, 2013), LYRM7 (Dallabona et al, 2016;Invernizzi et al, 2013), UQCC2 (Tucker et al, 2013), and UQCC3 (Wanschers et al, 2014). In particular, mutations in TTC19 have been identified in patients with heterogeneous, but invariably severe, phenotypes, including early-onset, slowly progressive encephalomyopathy; adult-onset, rapidly progressive multisystem neurological failure; adult-onset spinocerebellar ataxia; and childhood or juvenile spinocerebellar ataxia with psychosis (OMIM: 613814).…”

Section: Introductionmentioning

confidence: 99%

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TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III

et al. 2017

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Loss-of-function mutations in TTC19 (tetra-tricopeptide repeat domain 19) have been associated with severe neurological phenotypes and mitochondrial respiratory chain complex III deficiency. We previously demonstrated the mitochondrial localization of TTC19 and its link with complex III biogenesis. Here we provide detailed insight into the mechanistic role of TTC19, by investigating a Ttc19 mouse model that shows progressive neurological and metabolic decline, decreased complex III activity, and increased production of reactive oxygen species. By using both the Ttc19 mouse model and a range of human cell lines, we demonstrate that TTC19 binds to the fully assembled complex III dimer, i.e., after the incorporation of the iron-sulfur Rieske protein (UQCRFS1). The in situ maturation of UQCRFS1 produces N-terminal polypeptides, which remain bound to holocomplex III. We show that, in normal conditions, these UQCRFS1 fragments are rapidly removed, but when TTC19 is absent they accumulate within complex III, causing its structural and functional impairment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III

et al. 2017

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“…Since the first cases were reported, other TTC19 mutations have been published always associated with isolated CIII but with different clinical presentations. A progressive neurodegenerative disorder showing severe psychiatric signs and cerebellar disease was found in four Portuguese siblings born to consanguineous parents ( Nogueira et al, 2013 ), Leigh syndrome was reported in a Hispanic child ( Atwal, 2013 ) and cerebellar ataxia in Japanese adult individuals ( Morino et al, 2014 ; Kunii et al, 2015 ). All the described cases ( Table 2 ) carried non-sense or frameshift mutations leading to a truncated protein and, at least in the first reported patient samples, to undetectable TTC19 levels ( Ghezzi et al, 2011 ).…”

Section: Accessory Proteins: Assembly Factorsmentioning

confidence: 99%

Nuclear gene mutations as the cause of mitochondrial complex III deficiency

2015

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Complex III (CIII) deficiency is one of the least common oxidative phosphorylation defects associated to mitochondrial disease. CIII constitutes the center of the mitochondrial respiratory chain, as well as a crossroad for several other metabolic pathways. For more than 10 years, of all the potential candidate genes encoding structural subunits and assembly factors, only three were known to be associated to CIII defects in human pathology. Thus, leaving many of these cases unresolved. These first identified genes were MT-CYB, the only CIII subunit encoded in the mitochondrial DNA; BCS1L, encoding an assembly factor, and UQCRB, a nuclear-encoded structural subunit. Nowadays, thanks to the fast progress that has taken place in the last 3–4 years, pathological changes in seven more genes are known to be associated to these conditions. This review will focus on the strategies that have permitted the latest discovery of mutations in factors that are necessary for a correct CIII assembly and activity, in relation with their function. In addition, new data further establishing the molecular role of LYRM7/MZM1L as a chaperone involved in CIII biogenesis are provided.

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“…Recently, mutations in TTC19 have been described in young adults with spinocerebellar ataxia [ 2 - 4 ], a 42-year-old man with rapidly progressive neurological disease [ 1 ], and patients with developmental delay in childhood and slowly progressive neurodegenerative disease [ 1 , 5 , 6 ]. So far, 12 cases are documented in the literature.…”

Section: Introductionmentioning

confidence: 99%

Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype

Koch

Freisinger

Feichtinger

et al. 2015

Orphanet J Rare Dis

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BackgroundTTC19 deficiency is a progressive neurodegenerative disease associated with isolated mitochondrial respiratory chain (MRC) complex III deficiency and loss-of-function mutations in the TT19 gene in the few patients reported so far.MethodsWe performed exome sequencing and selective mutational analysis of TTC19, respectively, in patients from three unrelated families presenting with initially unspecific clinical signs of muscular hypotonia and global developmental delay followed by regression, ataxia, loss of speech, and rapid neurological deterioration. One patient showed severe lactic acidosis at the neonatal age and during intercurrent illness.ResultsWe identified homozygous mutations in all three index cases, in two families novel missense mutations (c.544 T > C/p.Leu185Pro; c.917 T > C/p.Leu324Pro). The younger sister of the severely affected patient 3 showed only mild delay of motor skills and muscular hypotonia so far but is also homozygous for the same mutation. Notably, one patient revealed normal activities of MRC complex III in two independent muscle biopsies. Neuroimaging of the severely affected patients demonstrated lesions in putamen and caudate nuclei, cerebellar atrophy, and the unusual finding of hypertrophic olivary nuclei degeneration. Reviewing the literature revealed striking similarities regarding neuroimaging and clinical course in pediatric patients with TTC19 deficiency: patterns consistent with Leigh or Leigh-like syndrome were found in almost all, hypertrophic olivary nucleus degeneration in all patients reported so far. The clinical course in pediatric patients is characterized by an initially unspecific developmental delay, followed by regression, progressive signs and symptoms of cerebellar, basal ganglia and brainstem affection, especially loss of speech and ataxia. Subsequently, neurological deterioration leading to a vegetative state occurs.ConclusionsOur findings add to the phenotypic, genetic, and biochemical spectrum of TTC19 deficiency. However, TTC19 deficient patients do show characteristic clinical and neuroimaging features, which may facilitate diagnosis of this yet rare disorder. Normal MRC complex III activity does not exclude the diagnosis.

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A Japanese case of cerebellar ataxia, spastic paraparesis and deep sensory impairment associated with a novel homozygous TTC19 mutation

Cited by 14 publications

References 27 publications

TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III

TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III

Nuclear gene mutations as the cause of mitochondrial complex III deficiency

Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype

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