Publications by authors named "Uwe Ahting"

36 Publications

The p.Ala2430Val mutation in filamin C causes a "hypertrophic myofibrillar cardiomyopathy".

J Muscle Res Cell Motil 2021 Mar 12. Epub 2021 Mar 12.

Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.

Hypertrophic cardiomyopathy (HCM) often leads to heart failure. Mutations in sarcomeric proteins are most frequently the cause of HCM but in many patients the gene defect is not known. Here we report on a young man who was diagnosed with HCM shortly after birth. Whole exome sequencing revealed a mutation in the FLNC gene (c.7289C > T; p.Ala2430Val) that was previously shown to cause aggregation of the mutant protein in transfected cells. Myocardial tissue from patients with this mutation has not been analyzed before and thus, the underlying etiology is not well understood. Myocardial tissue of our patient obtained during myectomy at the age of 23 years was analyzed in detail by histochemistry, immunofluorescence staining, electron microscopy and western blot analysis. Cardiac histology showed a pathology typical for myofibrillar myopathy with myofibril disarray and abnormal protein aggregates containing BAG3, desmin, HSPB5 and filamin C. Analysis of sarcomeric and intercalated disc proteins showed focally reduced expression of the gap junction protein connexin43 and Xin-positive sarcomeric lesions in the cardiomyocytes of our patient. In addition, autophagy pathways were altered with upregulation of LC3-II, WIPI1 and HSPB5, 6, 7 and 8. We conclude that the p.Ala2430Val mutation in FLNC most probably is associated with HCM characterized by abnormal intercalated discs, disarray of myofibrils and aggregates containing Z-disc proteins similar to myofibrillar myopathy, which supports the pathological effect of the mutation.
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http://dx.doi.org/10.1007/s10974-021-09601-1DOI Listing
March 2021

De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.

Brain 2021 03;144(2):411-419

Dr. v. Hauner Children's Hospital, Department of Pediatric Neurology and Developmental Medicine, LMU - University of Munich, 80337, Germany.

Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.
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http://dx.doi.org/10.1093/brain/awaa410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940174PMC
March 2021

Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal.

Nat Immunol 2020 05 23;21(5):555-566. Epub 2020 Apr 23.

Max Planck Institute of Biochemistry, Munich, Germany.

Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8 T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8 T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.
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http://dx.doi.org/10.1038/s41590-020-0666-9DOI Listing
May 2020

Homoplasmy of the Mitochondrial DNA Mutation m.616T>C Leads to Mitochondrial Tubulointerstitial Kidney Disease and Encephalopathia.

Nephron 2020 13;144(3):156-160. Epub 2019 Nov 13.

Division of Pediatric Nephrology, Ludwig-Maximilians University, Dr. v. Hauner Children's Hospital, Munich, Germany,

Autosomal-dominant tubulointerstitial kidney disease -(ADTKD) describes tubulointerstitial kidney disease with autosomal-dominant inheritance. In 2017, the term mitochondrial tubulointerstitial kidney disease (MITKD) was introduced for tubulointerstitial kidney disease caused by mitochondrial DNA (mtDNA) mutations. To date, there are few mutations described in literature causing MITKD, one of them is m.616T>C. A 5-year-old girl presented with chronic renal insufficiency and epilepsia. At the age of 3 years, status epileptic occurred and evolved into epilepsia partialis continua. At the age of 5 years, chronic renal failure (CKD II-III) was diagnosed due to tubulointerstitial kidney disease. Urine analysis showed elevated fractional excretions of sodium and chloride. Kidneys were enlarged and hyperechogenic. Blood pressure was elevated. The family history was unremarkable for renal and/or neurological disorders. Genetic testing was performed and revealed homoplasmy of the substitution m.616T>C in our patient's mtDNA. This mutation has been shown to cause chronic tubulointerstitial kidney disease leading to end-stage renal disease (ESRD) and epilepsia formerly. MITKD is a rare mitochondrial disease leading to ESRD and should be suggested in patients with epilepsia and renal insufficiency.
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http://dx.doi.org/10.1159/000504412DOI Listing
March 2021

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy.

Genet Med 2019 11 16;21(11):2521-2531. Epub 2019 May 16.

Department of Pathology, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada.

Purpose: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established.

Methods: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease.

Results: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration.

Conclusion: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
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http://dx.doi.org/10.1038/s41436-019-0532-zDOI Listing
November 2019

Mitochondrial DNA mutation analysis from exome sequencing-A more holistic approach in diagnostics of suspected mitochondrial disease.

J Inherit Metab Dis 2019 09 11;42(5):909-917. Epub 2019 Jun 11.

Institute of Human Genetics, Technical University München, Munich, Germany.

Diagnostics for suspected mitochondrial disease (MD) can be challenging and necessitate invasive procedures like muscle biopsy. This is due to the extremely broad genetic and phenotypic spectrum, disease genes on both nuclear and mitochondrial DNA (mtDNA), and the tissue specificity of mtDNA variants. Exome sequencing (ES) has revolutionized the diagnostics for MD. However, the nuclear and mtDNA are investigated with separate tests, increasing costs and duration of diagnostics. The full potential of ES is often not exploited as the additional analysis of "off-target reads" deriving from the mtDNA can be used to analyze both genomes. We performed mtDNA analysis by ES of 2111 cases in a clinical setting. We further assessed the recall rate and precision as well as the estimation of heteroplasmy by ES data by comparison with targeted mtDNA next generation sequencing in 49 cases. ES identified known pathogenic mtDNA point mutations in 38 individuals, increasing the diagnostic yield by nearly 2%. Analysis of mtDNA variants by ES had a high recall rate (96.2 ± 5.6%) and an excellent precision (99.5 ± 2.2%) when compared to the gold standard of targeted mtDNA next generation sequencing. ES estimated heteroplasmy levels with an average difference of 6.6 ± 3.8%, sufficient for clinical decision making. Taken together, the mtDNA analysis from ES is of sufficient quality for clinical diagnostics. We therefore propose ES, investigating both nuclear and mtDNA, as first line test in individuals with suspected MD. One should be aware, that a negative result does not exclude MD and necessitates further test (in additional tissues).
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http://dx.doi.org/10.1002/jimd.12109DOI Listing
September 2019

NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses.

Brain 2019 01;142(1):50-58

Institute of Human Genetics, Technische Universität München, Munich, Germany.

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.
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http://dx.doi.org/10.1093/brain/awy310DOI Listing
January 2019

Diverse phenotype in patients with complex I deficiency due to mutations in NDUFB11.

Eur J Med Genet 2019 Nov 10;62(11):103572. Epub 2018 Nov 10.

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia. Electronic address:

Mitochondrial complex I deficiency is the most frequent mitochondrial disorder presenting in childhood and the mutational spectrum is highly heterogeneous. The NDUFB11 gene is one of the recently identified genes, which is located in the short arm of the X-chromosome. Here we report clinical, biochemical, functional and genetic findings of two male patients with lactic acidosis, hypertrophic cardiomyopathy and isolated complex I deficiency due to de novo hemizygous mutations (c.286C > T and c.328C > T) in the NDUFB11 gene. Neither of them had any skin manifestations. The NDUFB11 gene encodes a relatively small integral membrane protein NDUFB11, which is essential for the assembly of an active complex I. The expression levels of this protein was decreased in both patient cells and a lentiviral complementation experiment also supported the notion that the complex I deficiency in those two patients is caused by NDUFB11 genetic defects. Our findings together with a review of the thirteen previously described patients demonstrate a wide spectrum of clinical features associated with NDUFB11-related complex I deficiency. However, histiocytoid cardiomyopathy and/or congenital sideroblastic anemia could be indicative for mutation in the NDUFB11 gene, while the clinical manifestation of the same mutation can be highly variable.
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http://dx.doi.org/10.1016/j.ejmg.2018.11.006DOI Listing
November 2019

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

Orphanet J Rare Dis 2018 07 19;13(1):120. Epub 2018 Jul 19.

Child Neurology, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy.

Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers.

Conclusions: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.
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http://dx.doi.org/10.1186/s13023-018-0784-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053715PMC
July 2018

PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum.

Neuropediatrics 2018 10 25;49(5):330-338. Epub 2018 Jun 25.

Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.

Background: Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic mutations.

Methods: Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms.

Results: We identified bi-allelic mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the gene and part of the neighboring gene.

Conclusions: deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.
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http://dx.doi.org/10.1055/s-0038-1661396DOI Listing
October 2018

Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G>A and m.14484T>C of the mitochondrial DNA.

Mitochondrion 2017 09 6;36:15-20. Epub 2016 Oct 6.

Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximilians-Universität München, Munich, Germany; DZNE-German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Electronic address:

Leber's hereditary optic neuropathy (LHON) is an inherited mitochondrial disease that usually leads to acute or subacute bilateral central vision loss. In 95% of cases, LHON is caused by one of three primary mutations of the mitochondrial DNA (mtDNA), m.11778G>A in the MT-ND4 gene, m.14484T>C in the MT-ND6 gene, or m.3460G>A in the MT-ND1 gene. Here we characterize clinically, genetically, and biochemically a LHON family with multiple patients harboring two of these primary LHON mutations, m.11778G>A homoplasmic and m.14484T>C heteroplasmic. The unusually low male-to-female ratio of affected family members is also seen among the other patients previously reported with two primary LHON mutations m.11778G>A and m.14484T>C. While the index patient had very late onset of symptoms at 75years and severe visual loss, her two daughters had both onset in childhood (6 and 9years), with moderate to mild visual loss. A higher degree of heteroplasmy of the m.14484T>C mutation was found to correlate with an earlier age at onset in this family. Ours is the first LHON family harboring two primary LHON mutations where functional studies were performed in several affected family members. A more pronounced bioenergetic defect was found to correlate with an earlier age at onset. The patient with the earliest age at onset had a more significant complex I dysfunction than all controls, including the LHON patient with only the m.11778G>A mutation, suggesting a synergistic effect of the two primary LHON mutations in this patient.
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http://dx.doi.org/10.1016/j.mito.2016.10.002DOI Listing
September 2017

Adult, isolated respiratory chain complex IV deficiency with minimal manifestations.

Folia Neuropathol 2015 ;53(2):153-7

Josef Finsterer, MD, PhD, Postfach 20, 1180 Vienna, Austria, phone: +43-1-71165-92085, fax: +43-1-4781711, e-mail:

Objectives: Isolated complex IV (cytochrome c oxidase) deficiency is one of the most frequent respiratory chain defects in mitochondrial disorders (MIDs) and usually occurs together with severe pediatric or rarely adult multisystem disease. Here we report an adult with isolated complex IV deficiency with unusually mild clinical manifestations.

Case Report: A 50-year-old man had developed generalized muscle aches and occasional twitching and stiffness of the musculature since age 48 years. He had a previous history of diabetes, acute hearing loss, hyperlipidemia, hyperuricemia, arterial hypertension, polyarthrosis, hypogonadism, and hypothyroidism. The family history was positive for diabetes (mother), CK elevation (brother), myalgias (brother), and proximal weakness of the upper limbs (mother). Work-up revealed hypoacusis, postural tremor and reduced tendon reflexes, recurrent mild hyper-CK-emia, neurogenic needle electromyography, and a muscle biopsy with mild non-specific changes. Biochemical investigations of the muscle homogenate revealed an isolated complex IV defect and reduced amounts of coenzyme Q (CoQ). He profited from CoQ supplementation, low-carbohydrate diet, and gluten-free diet.

Conclusions: Isolated complex IV deficiency may present with only mild muscular, endocrine, or cardiac manifestations in adults. Coenzyme Q supplementation, low-carbohydrate diet, and gluten-free diet may have a beneficial effect at least on some of the manifestations.
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http://dx.doi.org/10.5114/fn.2015.52412DOI Listing
December 2016

Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency.

Front Genet 2015 13;6:123. Epub 2015 Apr 13.

Institute of Human Genetics, Technische Universität München Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München Neuherberg, Germany.

Disorders of the mitochondrial energy metabolism are clinically and genetically heterogeneous. An increasingly recognized subgroup is caused by defective mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, with defects in 13 genes being linked to human disease to date. Mutations in three of them, NFU1, BOLA3, and IBA57, affect the assembly of mitochondrial [4Fe-4S] proteins leading to an impairment of diverse mitochondrial metabolic pathways and ATP production. Patients with defects in these three genes present with lactic acidosis, hyperglycinemia, and reduced activities of respiratory chain complexes I and II, the four lipoic acid-dependent 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). To date, five different NFU1 pathogenic variants have been reported in 15 patients from 12 families. We report on seven new patients from five families carrying compound heterozygous or homozygous pathogenic NFU1 mutations identified by candidate gene screening and exome sequencing. Six out of eight different disease alleles were novel and functional studies were performed to support the pathogenicity of five of them. Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients. Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration (seven out of seven). Our study contributes to a better definition of the phenotypic spectrum associated with NFU1 mutations and to the diagnostic workup of future patients.
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http://dx.doi.org/10.3389/fgene.2015.00123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394698PMC
April 2015

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

Orphanet J Rare Dis 2015 Apr 2;10:40. Epub 2015 Apr 2.

Department of Pediatrics, Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020, Salzburg, Austria.

Background: TTC19 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.

Methods: We 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.

Results: We 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.

Conclusions: Our 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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http://dx.doi.org/10.1186/s13023-015-0254-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422538PMC
April 2015

Spectrum of combined respiratory chain defects.

J Inherit Metab Dis 2015 Jul 17;38(4):629-40. Epub 2015 Mar 17.

Department of Paediatrics, Paracelsus Medical University, SALK Salzburg, Salzburg, 5020, Austria,

Inherited disorders of mitochondrial energy metabolism form a large and heterogeneous group of metabolic diseases. More than 250 gene defects have been reported to date and this number continues to grow. Mitochondrial diseases can be grouped into (1) disorders of oxidative phosphorylation (OXPHOS) subunits and their assembly factors, (2) defects of mitochondrial DNA, RNA and protein synthesis, (3) defects in the substrate-generating upstream reactions of OXPHOS, (4) defects in relevant cofactors and (5) defects in mitochondrial homeostasis. Deficiency of more than one respiratory chain enzyme is a common finding. Combined defects are found in 49 % of the known disease-causing genes of mitochondrial energy metabolism and in 57 % of patients with OXPHOS defects identified in our diagnostic centre. Combined defects of complexes I, III, IV and V are typically due to deficiency of mitochondrial DNA replication, RNA metabolism or translation. Defects in cofactors can result in combined defects of various combinations, and defects of mitochondrial homeostasis can result in a generalised decrease of all OXPHOS enzymes. Noteworthy, identification of combined defects can be complicated by different degrees of severity of each affected enzyme. Furthermore, even defects of single respiratory chain enzymes can result in combined defects due to aberrant formation of respiratory chain supercomplexes. Combined OXPHOS defects have a great variety of clinical manifestations in terms of onset, course severity and tissue involvement. They can present as classical encephalomyopathy but also with hepatopathy, nephropathy, haematologic findings and Perrault syndrome in a subset of disorders.
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http://dx.doi.org/10.1007/s10545-015-9831-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493854PMC
July 2015

COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency.

Am J Hum Genet 2015 Feb;96(2):309-17

Unit of Molecular Neurogenetics, Foundation of the Carlo Besta Neurological Institute, Istituto di Ricovero e Cura a Carettere Scientifico, 20126 Milan, Italy. Electronic address:

Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.
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http://dx.doi.org/10.1016/j.ajhg.2014.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320255PMC
February 2015

Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients.

Orphanet J Rare Dis 2014 Aug 20;9:119. Epub 2014 Aug 20.

Department of Genetics, Harvard Medical School, 77 Ave Louis Pasteur, Boston 02115, MA, USA.

Background: Sengers syndrome is an autosomal recessive condition characterized by congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the acylglycerol kinase (AGK) gene have been recently described as the cause of Sengers syndrome in nine families.

Methods: We investigated the clinical and molecular features of Sengers syndrome in seven new families; five families with the severe and two with the milder form.

Results: Sequence analysis of AGK revealed compound heterozygous or homozygous predicted loss-of-function mutations in all affected individuals. A total of eight different disease alleles were identified, of which six were novel, homozygous c.523_524delAT (p.Ile175Tyrfs*2), c.424-1G > A (splice site), c.409C > T (p.Arg137*) and c.877 + 3G > T (splice site), and compound heterozygous c.871C > T (p.Gln291*) and c.1035dup (p.Ile346Tyrfs*39). All patients displayed perinatal or early-onset cardiomyopathy and cataract, clinical features pathognomonic for Sengers syndrome. Other common findings included blood lactic acidosis and tachydyspnoea while nystagmus, eosinophilia and cervical meningocele were documented in only either one or two cases. Deficiency of the adenine nucleotide translocator was found in heart and skeletal muscle biopsies from two patients associated with respiratory chain complex I deficiency. In contrast to previous findings, mitochondrial DNA content was normal in both tissues.

Conclusion: We compare our findings to those in 21 previously reported AGK mutation-positive Sengers patients, confirming that Sengers syndrome is a clinically recognisable disorder of mitochondrial energy metabolism.
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http://dx.doi.org/10.1186/s13023-014-0119-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167147PMC
August 2014

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

Mol Genet Metab 2014 Mar 25;111(3):342-352. Epub 2013 Dec 25.

Department of Pediatrics, Inherited Metabolic Disease Centre, Klinikum Reutlingen, 72764 Reutlingen, Germany. Electronic address:

Defects of mitochondrial oxidative phosphorylation (OXPHOS) are associated with a wide range of clinical phenotypes and time courses. Combined OXPHOS deficiencies are mainly caused by mutations of nuclear genes that are involved in mitochondrial protein translation. Due to their genetic heterogeneity it is almost impossible to diagnose OXPHOS patients on clinical grounds alone. Hence next generation sequencing (NGS) provides a distinct advantage over candidate gene sequencing to discover the underlying genetic defect in a timely manner. One recent example is the identification of mutations in MTFMT that impair mitochondrial protein translation through decreased formylation of Met-tRNA(Met). Here we report the results of a combined exome sequencing and candidate gene screening study. We identified nine additional MTFMT patients from eight families who were affected with Leigh encephalopathy or white matter disease, microcephaly, mental retardation, ataxia, and muscular hypotonia. In four patients, the causal mutations were identified by exome sequencing followed by stringent bioinformatic filtering. In one index case, exome sequencing identified a single heterozygous mutation leading to Sanger sequencing which identified a second mutation in the non-covered first exon. High-resolution melting curve-based MTFMT screening in 350 OXPHPOS patients identified pathogenic mutations in another three index cases. Mutations in one of them were not covered by previous exome sequencing. All novel mutations predict a loss-of-function or result in a severe decrease in MTFMT protein in patients' fibroblasts accompanied by reduced steady-state levels of complex I and IV subunits. Being present in 11 out of 13 index cases the c.626C>T mutation is one of the most frequent disease alleles underlying OXPHOS disorders. We provide detailed clinical descriptions on eleven MTFMT patients and review five previously reported cases.
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http://dx.doi.org/10.1016/j.ymgme.2013.12.010DOI Listing
March 2014

Alterations of red cell membrane properties in neuroacanthocytosis.

PLoS One 2013 3;8(10):e76715. Epub 2013 Oct 3.

Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.

Neuroacanthocytosis (NA) refers to a group of heterogenous, rare genetic disorders, namely chorea acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington's disease-like 2 (HDL2) and pantothenate kinase associated neurodegeneration (PKAN), that mainly affect the basal ganglia and are associated with similar neurological symptoms. PKAN is also assigned to a group of rare neurodegenerative diseases, known as NBIA (neurodegeneration with brain iron accumulation), associated with iron accumulation in the basal ganglia and progressive movement disorder. Acanthocytosis, the occurrence of misshaped erythrocytes with thorny protrusions, is frequently observed in ChAc and MLS patients but less prevalent in PKAN (about 10%) and HDL2 patients. The pathological factors that lead to the formation of the acanthocytic red blood cell shape are currently unknown. The aim of this study was to determine whether NA/NBIA acanthocytes differ in their functionality from normal erythrocytes. Several flow-cytometry-based assays were applied to test the physiological responses of the plasma membrane, namely drug-induced endocytosis, phosphatidylserine exposure and calcium uptake upon treatment with lysophosphatidic acid. ChAc red cell samples clearly showed a reduced response in drug-induced endovesiculation, lysophosphatidic acid-induced phosphatidylserine exposure, and calcium uptake. Impaired responses were also observed in acanthocyte-positive NBIA (PKAN) red cells but not in patient cells without shape abnormalities. These data suggest an "acanthocytic state" of the red cell where alterations in functional and interdependent membrane properties arise together with an acanthocytic cell shape. Further elucidation of the aberrant molecular mechanisms that cause this acanthocytic state may possibly help to evaluate the pathological pathways leading to neurodegeneration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076715PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789665PMC
April 2014

Mitochondrial depletion syndromes in children and adults.

Can J Neurol Sci 2013 Sep;40(5):635-44

Krankenanstalt Rudolfstiftung, Vienna, Austria.

To highlight differences between early-onset and adult mitochondrial depletion syndromes (MDS) concerning etiology and genetic background, pathogenesis, phenotype, clinical presentation and their outcome. MDSs most frequently occur in neonates, infants, or juveniles and more rarely in adolescents or adults. Mutated genes phenotypically presenting with adult-onset MDS include POLG1, TK2, TyMP, RRM2B, or PEO1/twinkle. Adult MDS manifest similarly to early-onset MDS, as myopathy, encephalo-myopathy, hepato-cerebral syndrome, or with chronic progressive external ophthalmoplegia (CPEO), fatigue, or only minimal muscular manifestations. Diagnostic work-up or treatment is not at variance from early-onset cases. Histological examination of muscle may be normal but biochemical investigations may reveal multiple respiratory chain defects. The outcome appears to be more favorable in adult than in early-onset forms. Mitochondrial depletion syndromes is not only a condition of neonates, infants, or juveniles but rarely also occurs in adults, presenting with minimal manifestations or manifestations like in the early-onset forms. Outcome of adult-onset MDS appears more favorable than early-onset MDS.
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http://dx.doi.org/10.1017/s0317167100014852DOI Listing
September 2013

Adult mitochondrial DNA depletion syndrome with mild manifestations.

Neurol Int 2013 Jun 25;5(2):28-30. Epub 2013 Jun 25.

Krankenanstalt Rudolfstiftung , Vienna, Austria.

Mitochondrial DNA depletion syndrome (MDS) is usually a severe disorder of infancy or childhood, due to a reduced copy number of mtDNA molecules. MDS with only mild, nonspecific clinical manifestations and onset in adulthood has not been reported. A 47-year-old Caucasian female with short stature and a history of migraine, endometriosis, Crohn's disease, C-cell carcinoma of the thyroid gland, and a family history positive for mitochondrial disorder (2 sisters, aunt, niece), developed day-time sleepiness, exercise intolerance, and myalgias in the lower-limb muscles since age 46y. She slept 9-10 hours during the night and 2 hours after lunch daily. Clinical exam revealed sore neck muscles, bilateral ptosis, and reduced Achilles tendon reflexes exclusively. Blood tests revealed hyperlipidemia exclusively. Nerve conduction studies, needle electromyography, and cerebral and spinal magnetic resonance imaging were noninformative. Muscle biopsy revealed detached lobulated fibers with subsarcolemmal accentuation of the NADH and SDH staining. Realtime polymerase chain reaction revealed depletion of the mtDNA down to 9% of normal. MDS may be associated with a mild phenotype in adults and may not significantly progress during the first year after onset. In an adult with hypersomnia, severe tiredness, exercise intolerance, and a family history positive for mitochondrial disorder, a MDS should be considered.
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http://dx.doi.org/10.4081/ni.2013.e9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718249PMC
June 2013

Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome.

J Inherit Metab Dis 2012 Nov 3;35(6):943-8. Epub 2012 Aug 3.

Institute of Human Genetics, Technische Universität München, Trogerstrasse 22, München, 81675, Germany.

Brown-Vialetto-Van Laere syndrome (BVVLS [MIM 211530]) is a rare neurological disorder characterized by infancy onset sensorineural deafness and ponto-bulbar palsy. Mutations in SLC52A3 (formerly C20orf54), coding for riboflavin transporter 2 (hRFT2), have been identified as the molecular genetic correlate in several individuals with BVVLS. Exome sequencing of just one single case revealed that compound heterozygosity for two pathogenic mutations in the SLC52A2 gene coding for riboflavin transporter 3 (hRFT3), another member of the riboflavin transporter family, is also associated with BVVLS. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities. While mutations in SLC52A3 cause decreased plasma riboflavin levels, concordant with a role of SLC52A3 in riboflavin uptake from food, the SLC52A2-mutant individual had normal plasma riboflavin concentrations, a finding in line with a postulated function of SLC52A2 in riboflavin uptake from blood into target cells. Our results contribute to the understanding of human riboflavin metabolism and underscore its role in the pathogenesis of BVVLS, thereby providing a rational basis for a high-dose riboflavin treatment.
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http://dx.doi.org/10.1007/s10545-012-9513-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470687PMC
November 2012

Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing.

J Med Genet 2012 Apr;49(4):277-83

Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

Background: Next generation sequencing has become the core technology for gene discovery in rare inherited disorders. However, the interpretation of the numerous sequence variants identified remains challenging. We assessed the application of exome sequencing for diagnostics in complex I deficiency, a disease with vast genetic heterogeneity.

Methods: Ten unrelated individuals with complex I deficiency were selected for exome sequencing and sequential bioinformatic filtering. Cellular rescue experiments were performed to verify pathogenicity of novel disease alleles.

Results: The first filter criterion was 'Presence of known pathogenic complex I deficiency variants'. This revealed homozygous mutations in NDUFS3 and ACAD9 in two individuals. A second criterion was 'Presence of two novel potentially pathogenic variants in a structural gene of complex I', which discovered rare variants in NDUFS8 in two unrelated individuals and in NDUFB3 in a third. Expression of wild-type cDNA in mutant cell lines rescued complex I activity and assembly, thus providing a functional validation of their pathogenicity. Using the third criterion 'Presence of two potentially pathogenic variants in a gene encoding a mitochondrial protein', loss-of-function mutations in MTFMT were discovered in two patients. In three patients the molecular genetic correlate remained unclear and follow-up analysis is ongoing.

Conclusion: Appropriate in silico filtering of exome sequencing data, coupled with functional validation of new disease alleles, is effective in rapidly identifying disease-causative variants in known and new complex I associated disease genes.
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http://dx.doi.org/10.1136/jmedgenet-2012-100846DOI Listing
April 2012

Classical MERRF phenotype associated with mitochondrial tRNA(Leu) (m.3243A>G) mutation.

Eur J Pediatr 2012 May 25;171(5):859-62. Epub 2012 Jan 25.

Department of Pediatrics, Friedrich-Alexander-University of Erlangen-Nuremberg, Loschgestrasse 15, 91054, Erlangen, Germany.

Myoclonic epilepsy with ragged red fibres (MERRF) and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are established phenotypes of mitochondrial encephalopathies. Nearly all patients affected by MERRF harbour a mutation in the mitochondrial tRNA(Lys) gene. We report a 13-year-old patient who presented with the classical phenotype of MERRF but was found with the typical mutation of MELAS. The patient presented with myoclonic epilepsy beginning at 10 years of age, a muscle biopsy with ragged red fibres and some COX negative fibres and progressive bilateral MRI hyperintensitivities in the basal ganglia constituting MERRF syndrome but lacked clinical characteristics of MELAS. In particular, stroke-like episodes or lactic acidosis were not present. None of the tRNA mutations described in MERRF were found. However, further analyses showed the tRNA(Leu) mutation m.3243A>G usually found in MELAS to be responsible for the condition in this patient. This report highlights the broad phenotypic variability of mitochondrial encephalopathies with juvenile onset. It shows that m.3243A>G mutations can cause classical MERRF and emphasises the significance of comprehensive genetic studies if mitochondrial disease is suspected clinically.
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http://dx.doi.org/10.1007/s00431-011-1662-8DOI Listing
May 2012

Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9.

J Med Genet 2012 Feb 26;49(2):83-9. Epub 2011 Dec 26.

Institute of Human Genetics, Technische Universität München, Munich, Germany.

Background: Mitochondrial complex I deficiency is the most common cause of mitochondrial disease in childhood. Identification of the molecular basis is difficult given the clinical and genetic heterogeneity. Most patients lack a molecular definition in routine diagnostics.

Methods: A large-scale mutation screen of 75 candidate genes in 152 patients with complex I deficiency was performed by high-resolution melting curve analysis and Sanger sequencing. The causal role of a new disease allele was confirmed by functional complementation assays. The clinical phenotype of patients carrying mutations was documented using a standardised questionnaire.

Results: Causative mutations were detected in 16 genes, 15 of which had previously been associated with complex I deficiency: three mitochondrial DNA genes encoding complex I subunits, two mitochondrial tRNA genes and nuclear DNA genes encoding six complex I subunits and four assembly factors. For the first time, a causal mutation is described in NDUFB9, coding for a complex I subunit, resulting in reduction in NDUFB9 protein and both amount and activity of complex I. These features were rescued by expression of wild-type NDUFB9 in patient-derived fibroblasts.

Conclusion: Mutant NDUFB9 is a new cause of complex I deficiency. A molecular diagnosis related to complex I deficiency was established in 18% of patients. However, most patients are likely to carry mutations in genes so far not associated with complex I function. The authors conclude that the high degree of genetic heterogeneity in complex I disorders warrants the implementation of unbiased genome-wide strategies for the complete molecular dissection of mitochondrial complex I deficiency.
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http://dx.doi.org/10.1136/jmedgenet-2011-100577DOI Listing
February 2012

Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway.

Am J Hum Genet 2011 Dec;89(6):806-12

Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.

Thiamine pyrophosphate (TPP) is an essential cofactor of the cytosolic transketolase and of three mitochondrial enzymes involved in the oxidative decarboxylation of either pyruvate, α-ketoglutarate or branched chain amino acids. Thiamine is taken up by specific transporters into the cell and converted to the active TPP by thiamine pyrophosphokinase (TPK) in the cytosol from where it can be transported into mitochondria. Here, we report five individuals from three families presenting with variable degrees of ataxia, psychomotor retardation, progressive dystonia, and lactic acidosis. Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate but normal pyruvate dehydrogenase complex activity in the presence of excess TPP. A reduced concentration of TPP was found in the muscle and blood. Mutation analysis of TPK1 uncovered three missense, one splice-site, and one frameshift mutation resulting in decreased TPK protein levels.
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http://dx.doi.org/10.1016/j.ajhg.2011.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234371PMC
December 2011

Neurological phenotype and reduced lifespan in heterozygous Tim23 knockout mice, the first mouse model of defective mitochondrial import.

Biochim Biophys Acta 2009 May 9;1787(5):371-6. Epub 2008 Dec 9.

Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.

The Tim23 protein is the key component of the mitochondrial import machinery. It locates to the inner mitochondrial membrane and its own import is dependent on the DDP1/TIM13 complex. Mutations in human DDP1 cause the Mohr-Tranebjaerg syndrome (MTS/DFN-1; OMIM #304700), which is one of the two known human diseases of the mitochondrial protein import machinery. We created a Tim23 knockout mouse from a gene trap embryonic stem cell clone. Homozygous Tim23 mice were not viable. Heterozygous F1 mutants showed a 50% reduction of Tim23 protein in Western blot, a neurological phenotype and a markedly reduced life span. Haploinsufficiency of the Tim23 mutation underlines the critical role of the mitochondrial import machinery for maintaining mitochondrial function.
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http://dx.doi.org/10.1016/j.bbabio.2008.12.001DOI Listing
May 2009

MitoP2: an integrative tool for the analysis of the mitochondrial proteome.

Mol Biotechnol 2008 Nov 9;40(3):306-15. Epub 2008 Sep 9.

Institute of Human Genetics, Helmholtz Zentrum Munich - German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.

Mitochondria are crucial for normal cell metabolism and maintenance. Mitochondrial dysfunction has been implicated in a spectrum of human diseases, ranging from rare monogenic to common multifactorial disorders. Important for the understanding of organelle function is the assignment of its constituents, and although over 1,500 proteins are predicted to be involved in mammalian mitochondrial function, so far only about 900 are assigned to mitochondria with reasonable certainty. Continuing efforts are being taken to obtain a complete inventory of the mitochondrial proteome by single protein studies and high-throughput approaches. To be of best value for the scientific community this data needs to be structured, explored, and customized. For this purpose, the MitoP2 database ( http://www.mitop2.de ) was established and is maintained in order to incorporate such data. The central database contains manually evaluated yeast, mouse, and human reference proteins, which show convincing evidence of a mitochondrial location. In addition, entries from genome-wide approaches that suggest protein localization are integrated and serve to compile a combined score for each candidate, which provides a best estimate of mitochondrial localization. Furthermore, it integrates information on the orthology between species, including Saccharomyces cerevisiae, mouse, human, Arabidopsis thaliana, and Neurospora crassa, thus mutually enhancing evidence across species. In contrast to other known databases, MitoP2 takes into account the reliability by which the protein is estimated as being mitochondrially located, as described herein. Multiple search functions, as well as information on disease causing genes and available mouse models, makes MitoP2 a valuable tool for the genetic investigation of human mitochondrial pathology.
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http://dx.doi.org/10.1007/s12033-008-9100-5DOI Listing
November 2008

MitoP2, an integrated database for mitochondrial proteins.

Methods Mol Biol 2007 ;372:573-86

Institute of Human Genetics, Technical University of Munich, Germany.

The impact of mitochondria on several fundamental cellular processes is reflected in their involvement in the pathophysiology of common diseases such as Parkinson's disease, diabetes, and obesity and a wide range of monogenic disorders primarily associated with energy impairment or metabolic diseases. The importance of mitochondria is also reflected by the steep increase of proteins, which has been localized to this organelle. In yeast, more than 500 of the expected 700-800 mitochondrial proteins are already annotated. In the mammalian species, the expected numbers are estimated to be in the range of 1500-2000 proteins, and the currently annotated entries reach almost 700. In addition to the studies dealing with single proteins, there are many high-throughput approaches that improve the description of the mitochondrial proteome. They include computational predictions of signaling sequences, proteome mapping, mutant screening, expression profiling, protein-protein interaction, and cellular sublocalization studies. The MitoP2 database (http://www.mitop2.de/) was established to structure, explore, and customize the available data on mitochondrial proteins, functions, and diseases. MitoP2 provides a comprehensive picture of the mitochondrial proteome by focusing on (1) the orthology between species, including Saccharomyces cerevisiae, mouse, humans, and Arabidopsis thaliana; (2) the definition of mitochondrial reference sets in these species; (3) the integration of data predictive for mitochondrial localization or function stemming from genomewide approaches; (4) the allocation of a gateway for functional data from model systems and genetics of mitochondriopathies; and (5) the calculation of a combined score for each protein summarizing the indirect evidence for a mitochondrial localization. All data are accessible via search tools and linked to the original data source. By providing an overview of functional annotations from different databases, the MitoP2 database lends itself to genetic investigations of human mitochondriopathies.
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http://dx.doi.org/10.1007/978-1-59745-365-3_39DOI Listing
March 2008