Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening

Haack, Tobias B.; Gorza, Matteo; Danhauser, Katharina; Mayr, Johannes A.; Haberberger, Birgit; Wieland, Thomas; Kremer, Laura S.; Strecker, Valentina; Graf, Elisabeth; Memari, Yasin; Ahting, Uwe; Kopajtich, Robert; Wortmann, Saskia B.; Rodenburg, Richard J.; Kotzaeridou, Urania; Hoffmann, Georg F.; Sperl, Wolfgang; Wittig, Ilka; Wilichowski, Ekkehard; Schottmann, Gudrun; Schuelke, Markus; Plecko, Barbara; Stephani, Ulrich; Strom, Tim M.; Meitinger, Thomas; Prokisch, Holger; Freisinger, Peter

doi:10.1016/j.ymgme.2013.12.010

Cited by 66 publications

(71 citation statements)

References 32 publications

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“…7 Assuming an autosomal-recessive mode of inheritance, our analyses focused on homozygous and predictively compound heterozygous nonsynonymous variants with a MAFo0.1% in 4500 control exomes. This search identified 28 genes.…”

Section: Resultsmentioning

confidence: 99%

Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9

et al. 2015

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Coenzyme Q 10 (CoQ 10 ) has an important role in mitochondrial energy metabolism by way of its functioning as an electron carrier in the respiratory chain. Genetic defects disrupting the endogenous biosynthesis pathway of CoQ 10 may lead to severe metabolic disorders with onset in early childhood. Using exome sequencing in a child with fatal neonatal lactic acidosis and encephalopathy, we identified a homozygous loss-of-function variant in COQ9. Functional studies in patient fibroblasts showed that the absence of the COQ9 protein was concomitant with a strong reduction of COQ7, leading to a significant accumulation of the substrate of COQ7, 6-demethoxy ubiquinone 10 . At the same time, the total amount of CoQ 10 was severely reduced, which was reflected in a significant decrease of mitochondrial respiratory chain succinate-cytochrome c oxidoreductase (complex II/III) activity. Lentiviral expression of COQ9 restored all these parameters, confirming the causal role of the variant. Our report on the second COQ9 patient expands the clinical spectrum associated with COQ9 variants, indicating the importance of COQ9 already during prenatal development. Moreover, the rescue of cellular CoQ 10 levels and respiratory chain complex activities by CoQ 10 supplementation points to the importance of an early diagnosis and immediate treatment.

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Section: Resultsmentioning

confidence: 99%

Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9

et al. 2015

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“…Western blot analysis (SDS-PAGE) of oxidative phosphorylation enzymes was performed by blotting 10 mg of protein loaded on an SDS-polyacrylamide gel and probing with the respective antibodies as previously reported (Feichtinger et al 2014). A significant decrease was found in complex I in both patients tially as described in Haack et al 2014) revealed a known pathogenic hemizygous mutation c.281G>A, p. (Arg94His) in TAZ (RefSeq NM_000116). CL analysis in leucocytes was consistent with TAZ deficiency (CL 13 pmol/mg protein, normally >130, in Barth patients <30; monolyso-CL/CL ratio 3.43, normally <0.007, in Barth patients >2.52, performed as described in Bowron et al 2013).…”

Section: Patientmentioning

confidence: 99%

Atypical Clinical Presentations of TAZ Mutations: An Underdiagnosed Cause of Growth Retardation?

et al. 2015

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Barth syndrome is known as a highly recognizable X-linked disorder typically presenting with the three hallmarks: (left ventricular non-compaction) cardiomyopathy, neutropenia, and 3-methylglutaconic aciduria. Furthermore, growth retardation, mild skeletal myopathy, and specific facial features as well as mitochondrial dysfunction in muscle are frequently seen. Underlying mutations are found in TAZ and lead to defective cardiolipin remodeling.Here, we report atypical clinical manifestations of TAZ mutations in two male patients initially presenting with growth retardation and very mild skeletal myopathy. As other phenotypic hallmarks were missing, Barth syndrome had not been suspected in these patients. One of them has been incidentally diagnosed in the frame of an in-depth cardiolipin research analysis, while the underlying genetic defect was unexpectedly identified in the second one by exome sequencing.Conclusion: These cases underline that TAZ mutations might well be an underdiagnosed cause of skeletal myopathy and growth retardation and do not necessarily manifest with the full clinical picture of Barth syndrome.

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“…In lower eukaryotes such as S. cerevisiae, N-formylation is not essential (8). In humans, different compound heterozygous mutations in MTFMT were identified in a subset of patients diagnosed with Leigh syndrome, a severe neurometabolic disorder combined with OXPHOS dysfunction (9)(10)(11)(12)(13)(14)(15), demonstrating that N-formylation is critical for OXPHOS function. Furthermore, studies in fibroblasts of patients harboring mutations in the MTFMT gene showed reduced activity of complex I and/or IV and in some cases complex V supporting the critical role of Nformylation for mitochondrial OXPHOS function.…”

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Mitochondrial methionyl N-formylation affects steady-state levels of oxidative phosphorylation complexes and their organization into supercomplexes

Arguello

Köhrer

RajBhandary

et al. 2018

Journal of Biological Chemistry

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Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening

Cited by 66 publications

References 32 publications

Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9

Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9

Atypical Clinical Presentations of TAZ Mutations: An Underdiagnosed Cause of Growth Retardation?

Mitochondrial methionyl N-formylation affects steady-state levels of oxidative phosphorylation complexes and their organization into supercomplexes

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