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  • 1
    Language: English
    In: American journal of human genetics, 2014-01-02, Vol.94 (1), p.11-22
    Description: Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA.
    Subject(s): Brain ; Brain - drug effects ; Brain - pathology ; Cloning, Molecular ; Coenzyme A - metabolism ; DNA sequencing ; Escherichia coli - genetics ; Exome ; Female ; Fibroblasts - metabolism ; Gene Expression Regulation ; Gene mutations ; Genetic aspects ; Humans ; Iron - metabolism ; Iron in the body ; Male ; Mitochondria - enzymology ; Mitochondria - genetics ; Mutation, Missense ; Nerve Degeneration - pathology ; Neurogenetics ; Nucleotide sequencing ; Pantetheine - analogs & derivatives ; Pantetheine - metabolism ; Pedigree ; Phosphorylation ; Physiological aspects ; Research ; Saccharomyces cerevisiae - genetics ; Transferases - genetics ; Transferases - metabolism
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 2
    Language: English
    In: American journal of human genetics, 2016-12-01, Vol.99 (6), p.1377-1387
    Description: Early-onset generalized dystonia represents the severest form of dystonia, a hyperkinetic movement disorder defined by involuntary twisting postures. Although frequently transmitted as a single-gene trait, the molecular basis of dystonia remains largely obscure. By whole-exome sequencing a parent-offspring trio in an Austrian kindred affected by non-familial early-onset generalized dystonia, we identified a dominant de novo frameshift mutation, c.6406delC (p.Leu2136Serfs∗17), in KMT2B, encoding a lysine-specific methyltransferase involved in transcriptional regulation via post-translational modification of histones. Whole-exome-sequencing-based exploration of a further 30 German-Austrian individuals with early-onset generalized dystonia uncovered another three deleterious mutations in KMT2B—one de novo nonsense mutation (c.1633C〉T [p.Arg545∗]), one de novo essential splice-site mutation (c.7050−2A〉G [p.Phe2321Serfs∗93]), and one inherited nonsense mutation (c.2428C〉T [p.Gln810∗]) co-segregating with dystonia in a three-generation kindred. Each of the four mutations was predicted to mediate a loss-of-function effect by introducing a premature termination codon. Suggestive of haploinsufficiency, we found significantly decreased total mRNA levels of KMT2B in mutant fibroblasts. The phenotype of individuals with KMT2B loss-of-function mutations was dominated by childhood lower-limb-onset generalized dystonia, and the family harboring c.2428C〉T (p.Gln810∗) showed variable expressivity. In most cases, dystonic symptoms were accompanied by heterogeneous non-motor features. Independent support for pathogenicity of the mutations comes from the observation of high rates of dystonic presentations in KMT2B-involving microdeletion syndromes. Our findings thus establish generalized dystonia as the human phenotype associated with haploinsufficiency of KMT2B. Moreover, we provide evidence for a causative role of disordered histone modification, chromatin states, and transcriptional deregulation in dystonia pathogenesis.
    Subject(s): Adolescent ; Adult ; Age of Onset ; Base Sequence ; Child ; Dystonia ; Dystonic Disorders - genetics ; Female ; Gene mutations ; Genetic aspects ; Haploinsufficiency - genetics ; Health aspects ; Histone-Lysine N-Methyltransferase - genetics ; Humans ; Lysine - metabolism ; Male ; Methyltransferases ; Pedigree ; Report ; Young Adult
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 3
    Language: English
    In: American journal of human genetics, 2012-06-08, Vol.90 (6), p.1079-1087
    Description: Dysfunction of mitochondrial respiration is an increasingly recognized cause of isolated hypertrophic cardiomyopathy. To gain insight into the genetic origin of this condition, we used next-generation exome sequencing to identify mutations in MTO1, which encodes mitochondrial translation optimization 1. Two affected siblings carried a maternal c.1858dup (p.Arg620Lysfs∗8) frameshift and a paternal c.1282G〉A (p.Ala428Thr) missense mutation. A third unrelated individual was homozygous for the latter change. In both humans and yeast, MTO1 increases the accuracy and efficiency of mtDNA translation by catalyzing the 5-carboxymethylaminomethylation of the wobble uridine base in three mitochondrial tRNAs (mt-tRNAs). Accordingly, mutant muscle and fibroblasts showed variably combined reduction in mtDNA-dependent respiratory chain activities. Reduced respiration in mutant cells was corrected by expressing a wild-type MTO1 cDNA. Conversely, defective respiration of a yeast mto1Δ strain failed to be corrected by an Mto1Pro622∗ variant, equivalent to human MTO1Arg620Lysfs∗8, whereas incomplete correction was achieved by an Mto1Ala431Thr variant, corresponding to human MTO1Ala428Thr. The respiratory yeast phenotype was dramatically worsened in stress conditions and in the presence of a paromomycin-resistant (PR) mitochondrial rRNA mutation. Lastly, in vivo mtDNA translation was impaired in the mutant yeast strains.
    Subject(s): Acidosis, Lactic - genetics ; Base Sequence ; Biological and medical sciences ; Cardiology. Vascular system ; Cardiomyopathy, Hypertrophic ; Cardiomyopathy, Hypertrophic - genetics ; Carrier Proteins - genetics ; Causes of ; DNA Mutational Analysis ; DNA, Mitochondrial - genetics ; Fibroblasts - metabolism ; Fundamental and applied biological sciences. Psychology ; Gene mutations ; Genetic aspects ; Genetic translation ; Genetics of eukaryotes. Biological and molecular evolution ; Heart ; Homozygote ; Humans ; Lactic acidosis ; Medical genetics ; Medical sciences ; Mitochondria ; Mitochondria - metabolism ; Mitochondrial DNA ; Molecular and cellular biology ; Molecular Sequence Data ; Mothers ; Mutation ; Mutation, Missense ; Myocarditis. Cardiomyopathies ; Nucleic Acid Conformation ; Oxidative Phosphorylation ; Paromomycin - pharmacology ; Phenotype ; Phosphorylation ; Report ; Research ; Respiration ; RNA, Ribosomal - metabolism ; RNA, Transfer - genetics ; Saccharomyces cerevisiae - genetics ; Transfer RNA
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Cell Press Collection [ECCPC]
    Source: PubMed Central
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  • 4
    Language: English
    In: Journal of medical genetics, 2012-02, Vol.49 (2), p.83-89
    Description: BackgroundMitochondrial 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.MethodsA 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.ResultsCausative 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.ConclusionMutant 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.
    Subject(s): Biological and medical sciences ; clinical genetics ; Complex I ; DNA Mutational Analysis ; Electron Transport Complex I - deficiency ; Electron Transport Complex I - genetics ; endocrinology ; Fundamental and applied biological sciences. Psychology ; General aspects. Genetic counseling ; Genes, Mitochondrial ; Genetic Heterogeneity ; genetic screening/counselling ; genetics ; Genetics of eukaryotes. Biological and molecular evolution ; high resolution melting curve analysis ; High-Throughput Screening Assays ; Humans ; lentiviral complementation ; Medical genetics ; Medical sciences ; metabolic disorders ; Mitochondrial complex I deficiency ; Mitochondrial Diseases - diagnosis ; Mitochondrial Diseases - genetics ; Molecular and cellular biology ; molecular genetics ; muscle disease ; Mutation ; NADH Dehydrogenase - genetics ; NADH Dehydrogenase - metabolism ; NDUFB9 ; neurology ; neuromuscular disease ; neurosciences ; Phenotype
    ISSN: 0022-2593
    E-ISSN: 1468-6244
    Source: Hellenic Academic Libraries Link
    Source: BMJ Journals - NESLi2
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  • 5
    Language: English
    In: American journal of human genetics, 2012-02-10, Vol.90 (2), p.314-320
    Description: Exome sequencing of an individual with congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis, all typical symptoms of Sengers syndrome, discovered two nonsense mutations in the gene encoding mitochondrial acylglycerol kinase (AGK). Mutation screening of AGK in further individuals with congenital cataracts and cardiomyopathy identified numerous loss-of-function mutations in an additional eight families, confirming the causal nature of AGK deficiency in Sengers syndrome. The loss of AGK led to a decrease of the adenine nucleotide translocator in the inner mitochondrial membrane in muscle, consistent with a role of AGK in driving the assembly of the translocator as a result of its effects on phospholipid metabolism in mitochondria.
    Subject(s): Adult ; Alleles ; Biological and medical sciences ; Cardiomyopathies - enzymology ; Cardiomyopathies - genetics ; Cataract - enzymology ; Cataract - genetics ; Child ; Codon, Nonsense ; Exome ; Female ; Fundamental and applied biological sciences. Psychology ; General aspects. Genetic counseling ; Genes ; Genetic disorders ; Genetics of eukaryotes. Biological and molecular evolution ; Heterozygote ; Humans ; Infant ; Infant, Newborn ; Male ; Medical genetics ; Medical sciences ; Mitochondria - enzymology ; Mitochondria - genetics ; Mitochondrial ADP, ATP Translocases - genetics ; Mitochondrial DNA ; Mitochondrial Proteins - deficiency ; Mitochondrial Proteins - genetics ; Molecular and cellular biology ; Muscles - metabolism ; Phenotype ; Phospholipids - metabolism ; Phosphotransferases (Alcohol Group Acceptor) - deficiency ; Phosphotransferases (Alcohol Group Acceptor) - genetics ; Purines ; Report ; Young Adult
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Cell Press Collection [ECCPC]
    Source: PubMed Central
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  • 6
    Language: English
    In: American journal of human genetics, 2014-12-04, Vol.95 (6), p.689-697
    Description: Diabetes mellitus and neurodegeneration are common diseases for which shared genetic factors are still only partly known. Here, we show that loss of the BiP (immunoglobulin heavy-chain binding protein) co-chaperone DNAJC3 leads to diabetes mellitus and widespread neurodegeneration. We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy. Exome sequencing identified a homozygous stop mutation in DNAJC3. Screening of a diabetes database with 226,194 individuals yielded eight phenotypically similar individuals and one family carrying a homozygous DNAJC3 deletion. DNAJC3 was absent in fibroblasts from all affected subjects in both families. To delineate the phenotypic and mutational spectrum and the genetic variability of DNAJC3, we analyzed 8,603 exomes, including 506 from families affected by diabetes, ataxia, upper-motor-neuron damage, peripheral neuropathy, or hearing loss. This analysis revealed only one further loss-of-function allele in DNAJC3 and no further associations in subjects with only a subset of the features of the main phenotype. Our findings demonstrate that loss-of-function DNAJC3 mutations lead to a monogenic, recessive form of diabetes mellitus in humans. Moreover, they present a common denominator for diabetes and widespread neurodegeneration. This complements findings from mice in which knockout of Dnajc3 leads to diabetes and modifies disease in a neurodegenerative model of Marinesco-Sjögren syndrome.
    Subject(s): Adolescent ; Adult ; Ataxia - genetics ; Causes of ; Degeneration ; Diabetes ; Diabetes Mellitus, Type 1 - diagnostic imaging ; Diabetes Mellitus, Type 1 - genetics ; Exome - genetics ; Female ; Fibroblasts ; Gene Expression Regulation ; Health aspects ; Heat-Shock Proteins - genetics ; Homozygote ; HSP40 Heat-Shock Proteins - genetics ; HSP40 Heat-Shock Proteins - metabolism ; Humans ; Male ; Models, Molecular ; Molecular chaperones ; Multiple System Atrophy - diagnostic imaging ; Multiple System Atrophy - genetics ; Mutation ; Nervous system ; Pedigree ; Phenotype ; Radiography ; Report ; Sequence Analysis, DNA ; Young Adult
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 7
    Language: English
    In: American journal of human genetics, 2013-08-08, Vol.93 (2), p.211-223
    Description: The human mitochondrial genome encodes RNA components of its own translational machinery to produce the 13 mitochondrial-encoded subunits of the respiratory chain. Nuclear-encoded gene products are essential for all processes within the organelle, including RNA processing. Transcription of the mitochondrial genome generates large polycistronic transcripts punctuated by the 22 mitochondrial (mt) tRNAs that are conventionally cleaved by the RNase P-complex and the RNase Z activity of ELAC2 at 5′ and 3′ ends, respectively. We report the identification of mutations in ELAC2 in five individuals with infantile hypertrophic cardiomyopathy and complex I deficiency. We observed accumulated mtRNA precursors in affected individuals muscle and fibroblasts. Although mature mt-tRNA, mt-mRNA, and mt-rRNA levels were not decreased in fibroblasts, the processing defect was associated with impaired mitochondrial translation. Complementation experiments in mutant cell lines restored RNA processing and a yeast model provided additional evidence for the disease-causal role of defective ELAC2, thereby linking mtRNA processing to human disease.
    Subject(s): Amino Acid Sequence ; Cardiomyopathy ; Cardiomyopathy, Hypertrophic - genetics ; Cardiomyopathy, Hypertrophic - metabolism ; Cardiomyopathy, Hypertrophic - pathology ; Cell Nucleus - genetics ; Cell Nucleus - metabolism ; Electron Transport - genetics ; Endoribonucleases - genetics ; Endoribonucleases - metabolism ; Female ; Fibroblasts - metabolism ; Fibroblasts - pathology ; Gene mutations ; Genetic aspects ; Genetic Complementation Test ; Heart diseases ; Heart enlargement ; Humans ; Infant ; Male ; Mitochondria - genetics ; Mitochondria - metabolism ; Molecular Sequence Data ; Muscles - metabolism ; Muscles - pathology ; Mutation ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Pedigree ; Physiological aspects ; Research ; RNA Processing, Post-Transcriptional ; RNA sequencing ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; RNA, Ribosomal - genetics ; RNA, Ribosomal - metabolism ; RNA, Transfer - genetics ; RNA, Transfer - metabolism ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae - metabolism
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Cell Press Collection [ECCPC]
    Source: PubMed Central
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  • 8
    Language: English
    In: International journal of molecular sciences, 2021-05-20, Vol.22 (10), p.5396
    Description: Mutations in POC1B are a rare cause of inherited retinal degeneration. In this study, we present a thorough phenotypic and genotypic characterization of three individuals harboring putatively pathogenic variants in the POC1B gene. All patients displayed a similar, slowly progressive retinopathy (cone dystrophy or cone-rod dystrophy) with normal funduscopy but disrupted outer retinal layers on optical coherence tomography and variable age of onset. Other symptoms were decreased visual acuity and photophobia. Whole genome sequencing revealed a novel homozygous frameshift variant in one patient. Another patient was shown to harbor a novel deep intronic variant in compound heterozygous state with a previously reported canonical splice site variant. The third patient showed a novel nonsense variant and a novel non-canonical splice site variant. We aimed to validate the effect of the deep intronic variant and the non-canonical splice site variant by means of in vitro splice assays. In addition, direct RNA analysis was performed in one patient. Splicing analysis revealed that the non-canonical splice site variant c.561-3T〉C leads to exon skipping while the novel deep intronic variant c.1033-327T〉A causes pseudoexon activation. Our data expand the genetic landscape of POC1B mutations and confirm the benefit of genome sequencing in combination with downstream functional validation using minigene assays for the analysis of putative splice variants. In addition, we provide clinical multimodal phenotyping of the affected individuals.
    Subject(s): cone dystrophy ; cone-rod dystrophy ; deep intronic splice variant ; in vitro splice assay ; non-canonical splice site variant ; POC1B
    ISSN: 1422-0067
    ISSN: 1661-6596
    E-ISSN: 1422-0067
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 9
    Language: English
    In: Journal of cutaneous pathology, 2021-11-07
    ISSN: 0303-6987
    E-ISSN: 1600-0560
    Source: Hellenic Academic Libraries Link
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  • 10
    Language: English
    In: American journal of human genetics, 2016-10-06, Vol.99 (4), p.894-902
    Description: To safeguard the cell from the accumulation of potentially harmful metabolic intermediates, specific repair mechanisms have evolved. APOA1BP, now renamed NAXE, encodes an epimerase essential in the cellular metabolite repair for NADHX and NADPHX. The enzyme catalyzes the epimerization of NAD(P)HX, thereby avoiding the accumulation of toxic metabolites. The clinical importance of the NAD(P)HX repair system has been unknown. Exome sequencing revealed pathogenic biallelic mutations in NAXE in children from four families with (sub-) acute-onset ataxia, cerebellar edema, spinal myelopathy, and skin lesions. Lactate was elevated in cerebrospinal fluid of all affected individuals. Disease onset was during the second year of life and clinical signs as well as episodes of deterioration were triggered by febrile infections. Disease course was rapidly progressive, leading to coma, global brain atrophy, and finally to death in all affected individuals. NAXE levels were undetectable in fibroblasts from affected individuals of two families. In these fibroblasts we measured highly elevated concentrations of the toxic metabolite cyclic-NADHX, confirming a deficiency of the mitochondrial NAD(P)HX repair system. Finally, NAD or nicotinic acid (vitamin B3) supplementation might have therapeutic implications for this fatal disorder.
    Subject(s): Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Causes of ; Cell Line ; Child, Preschool ; Children ; Diseases ; energy metabolism ; Fatal Outcome ; Female ; Fibroblasts ; Gene mutations ; Genetic aspects ; Health aspects ; Humans ; Infant ; Male ; Metabolic diseases ; Metabolic Diseases - genetics ; Metabolic Diseases - metabolism ; Metabolic Diseases - pathology ; Metabolic disorders in children ; metabolite repair ; mitochondrial ; Mutation ; NAD - analogs & derivatives ; NAD - metabolism ; NAD(P)HX ; Nervous System Diseases - genetics ; Nervous System Diseases - metabolism ; Nervous System Diseases - pathology ; Neuroimaging ; Racemases and Epimerases - genetics ; Report ; Skin Abnormalities - genetics ; Skin Abnormalities - pathology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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