Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis

Catania, Alessia; Ardissone, Anna; Verrigni, Daniela; Legati, Andrea; Reyes, Aurelio; Lamantea, Eleonora; Diodato, Daria; Tonduti, Davide; Imperatore, Valentina; Pinto, Anna Maria; Moroni, Isabella; Bertini, Enrico; Robinson, Alan J.; Carrozzo, Rosalba; Zeviani, Massimo; Ghezzi, Daniele

doi:10.1038/s10038-018-0423-1

Cited by 14 publications

(10 citation statements)

References 8 publications

(16 reference statements)

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“…All patients showed basal ganglia neurodegeneration on MRI. In two patients, a similar progression of basal ganglia abnormalities was reported with acute restricted diffusion lesions in the putamen spreading to the caudate and leading to atrophy and cavitation [45,46]. Three patients associated lesions in the cerebellar peduncles and dentate nuclei, and one single case showed involvement of the pons and parietal white matter.…”

Section: Discussionsupporting

confidence: 63%

“…All patients showed basal ganglia lesions on MRI, predominantly affecting the putamen and caudate. T2-hyperintensities in dentate nuclei and superior cerebellar peduncles were observed in three patients [45,46]. One patient showed a more diffuse brain involvement, with lesions affecting the parietal cerebral white matter and the dorsal pons [23].…”

Section: Literature Review Of Patients With Ndufaf6 Deficiencymentioning

confidence: 96%

“…Our patients were compared with 11 previously reported cases with NDUFAF6 defects and LS phenotype [23,25,[45][46][47] (Table 1). Mean age at onset of these children was 24 (0-72) months.…”

Section: Literature Review Of Patients With Ndufaf6 Deficiencymentioning

confidence: 99%

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Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood

Baide‐Mairena

Gaudó

Martí-Sánchez

et al. 2019

Molecular Genetics and Metabolism

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To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations. Method: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts. Results: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T > C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival. Interpretation: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.

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Section: Discussionsupporting

confidence: 63%

Section: Literature Review Of Patients With Ndufaf6 Deficiencymentioning

confidence: 96%

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Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood

Baide‐Mairena

Gaudó

Martí-Sánchez

et al. 2019

Molecular Genetics and Metabolism

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“…As with the deficits originated from mutations in the nuclear-encoded structural subunits, the syndromes associated with cI assembly factors usually present early in childhood. The most typical clinical feature is encephalopathy but also cardiomyopathy and, less frequently, hepatic and renal involvement (Table 1 [60][61][62][63][64] is also thought to assist in the assembly of the Q-module and maintain normal levels of the structural subunit MT-ND1 [28, 61,65]. Both NDUFAF5 (C20ORF7) and NDUFAF7 are modifying enzymes of subunits of the Qmodule, catalyzing the hydroxylation of NDUFS7 and the dimethylation of NDUFS2, respectively [66,67].…”

Section: Mutations In Factors and Chaperones Regulating Complex I Assemblymentioning

confidence: 99%

Mitochondrial disorders of the OXPHOS system

2020

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Mitochondrial disorders are amongst the most frequent inborn errors of metabolism, their primary cause being the dysfunction of the oxidative phosphorylation system (OXPHOS). OXPHOS is composed of the electron transport chain (ETC), formed by four multimeric enzymes and two mobile electron carriers, plus an ATP synthase (also called complex V). The ETC performs the redox reactions involved in cellular respiration while generating the proton motive force used by complex V to synthesize ATP. OXPHOS biogenesis involves multiple steps, starting from the expression of genes encoded in physically separated genomes, namely the mitochondrial and nuclear DNA, to the coordinated assembly of components and cofactors building each individual complex and eventually the supercomplexes. The genetic cause underlying around half of the diagnosed mitochondrial disease cases is currently known. Many of these cases result from pathogenic variants in genes encoding structural subunits or additional factors directly involved in the assembly of the ETC complexes. Here we review the historical and most recent findings concerning the clinical phenotypes and the molecular pathological mechanisms underlying this particular group of disorders.

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“…The associated SNPs are located in noncoding regions of the TP63 gene with unknown clinical significance at this time thus precluding interpretation of the potential effects of each variant on AP pathogenesis. However, evidence is emerging that noncoding variants might interfere with gene splicing, leading to aberrant mRNA transcripts and the formation of nonfunctional proteins (Petersen et al 2013, Catania et al 2018).…”

Section: )mentioning

confidence: 99%

Potential role of TP63 in apical periodontitis development

et al. 2019

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Aim To investigate the expression of TP63 in apical periodontitis (AP) tissues and the association of single nucleotide polymorphisms (SNPs) in the TP63 gene with AP using a case‐control dataset. Methodology Expression of TP63 in human AP lesions (apical abscess, radicular cyst, periapical granuloma) was evaluated using immunohistochemistry. A case‐control association study was performed to assess the association of TP63 polymorphisms in individuals having AP with or without associated pain. Cases were defined as subjects with deep caries and AP (n = 151) and subjects with symptomatic apical periodontitis or acute apical abscess (n = 124). Subjects without AP (n = 169) and asymptomatic (n = 196) were used as controls, respectively. Saliva samples were collected as source of genomic DNA. Twelve SNPs in the TP63 gene were selected for genotyping using Taqman chemistry in real‐time PCR. Data analysis was performed using PLINK software. The Bonferroni method was applied to correct for multiple testing; α ≤ 0.004 indicates significant differences between groups. Results TP63 expression was evident in apical abscesses and radicular cysts, while weaker expression was observed in periapical granulomas. Positive expression was observed in mononuclear cells in the granulation tissues of all AP lesions. Regarding the presence of AP, a trend for allelic association was observed for rs16864812 and rs9810322 (P = 0.04) and rs9810322 genotypes were also nominally associated with AP under a dominant model (P = 0.04). When considering the presence of periapical pain, a trend for allelic and genotypic association was observed for rs10155037 (P = 0.03). Haplotypes were also associated with AP and periapical pain (P ≤ 0.05). Conclusions Apical periodontitis is a complex multifactorial condition and it is likely that multiple genes and environmental effects may influence its susceptibility, progression or both. TP63 variants may play a role in AP pathogenesis and susceptibility, individually or interactively with other genes. Additional studies in other populations and functional studies are needed to improve understanding of the role of TP63 in AP.

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Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis

Cited by 14 publications

References 8 publications

Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood

Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood

Mitochondrial disorders of the OXPHOS system

Potential role of TP63 in apical periodontitis development

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