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  • 1
    Language: English
    In: eLife, 2016-08-06, Vol.5
    Description: Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans.
    Subject(s): Ataxia ; ATPases Associated with Diverse Cellular Activities ; Atrophy ; Biopsy ; Conserved sequence ; Deoxyribonucleic acid ; Disease ; DNA ; Family medical history ; Female ; Fibroblasts ; Genetic testing ; Genetics ; Homozygote ; Human ; Human Biology and Medicine ; Humans ; intellectual disability ; Life Sciences ; Male ; Medical research ; Medicine ; Metalloendopeptidases - genetics ; Microscopy ; Missense mutation ; Mitochondria ; Mitochondria - pathology ; Mitochondrial Diseases - genetics ; Mitochondrial DNA ; mitochondrial fragmentation ; Mitochondrial processing peptidase ; Mitochondrial Proteins ; mitochondriopathy ; Morphology ; Mouse ; Mutation ; Mutation, Missense ; Neurosciences ; OPA1 ; Optic atrophy ; Optic Atrophy - genetics ; Optic nerve ; Patients ; Pedigree ; Peptidase ; Proteins ; Software ; Yeast ; YME1L1
    ISSN: 2050-084X
    E-ISSN: 2050-084X
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: Nucleic acids research, 2019-07-02, Vol.47 (W1), p.W114-W120
    Description: MutationDistiller is a freely available online tool for user-driven analyses of Whole Exome Sequencing data. It offers a user-friendly interface aimed at clinicians and researchers, who are not necessarily bioinformaticians. MutationDistiller combines MutationTaster's pathogenicity predictions with a phenotype-based approach. Phenotypic information is not limited to symptoms included in the Human Phenotype Ontology (HPO), but may also comprise clinical diagnoses and the suspected mode of inheritance. The search can be restricted to lists of candidate genes (e.g. virtual gene panels) and by tissue-specific gene expression. The inclusion of GeneOntology (GO) and metabolic pathways facilitates the discovery of hitherto unknown disease genes. In a novel approach, we trained MutationDistiller's HPO-based prioritization on authentic genotype-phenotype sets obtained from ClinVar and found it to match or outcompete current prioritization tools in terms of accuracy. In the output, the program provides a list of potential disease mutations ordered by the likelihood of the affected genes to cause the phenotype. MutationDistiller provides links to gene-related information from various resources. It has been extensively tested by clinicians and their suggestions have been valued in many iterative cycles of revisions. The tool, a comprehensive documentation and examples are freely available at https://www.mutationdistiller.org/
    Subject(s): Biochemistry & Molecular Biology ; Databases, Genetic ; DNA - genetics ; Exome - genetics ; Genetic Diseases, Inborn - genetics ; Genetic Variation - genetics ; Humans ; Life Sciences & Biomedicine ; Mutation - genetics ; Phenotype ; Science & Technology ; Software ; User-Computer Interface ; Web Server Issue ; Whole Exome Sequencing
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 3
    Language: English
    In: American journal of human genetics, 2020-06-04, Vol.106 (6), p.872-884
    Description: Genome-wide analysis methods, such as array comparative genomic hybridization (CGH) and whole-genome sequencing (WGS), have greatly advanced the identification of structural variants (SVs) in the human genome. However, even with standard high-throughput sequencing techniques, complex rearrangements with multiple breakpoints are often difficult to resolve, and predicting their effects on gene expression and phenotype remains a challenge. Here, we address these problems by using high-throughput chromosome conformation capture (Hi-C) generated from cultured cells of nine individuals with developmental disorders (DDs). Three individuals had previously been identified as harboring duplications at the SOX9 locus and six had been identified with translocations. Hi-C resolved the positions of the duplications and was instructive in interpreting their distinct pathogenic effects, including the formation of new topologically associating domains (neo-TADs). Hi-C was very sensitive in detecting translocations, and it revealed previously unrecognized complex rearrangements at the breakpoints. In several cases, we observed the formation of fused-TADs promoting ectopic enhancer-promoter interactions that were likely to be involved in the disease pathology. In summary, we show that Hi-C is a sensible method for the detection of complex SVs in a clinical setting. The results help interpret the possible pathogenic effects of the SVs in individuals with DDs.
    Subject(s): Analysis ; Chromatin Assembly and Disassembly - genetics ; Chromosome Breakpoints ; chromosome conformation capture ; Chromosomes, Human - genetics ; Cohort Studies ; Cytogenetics ; Developmental Disabilities - genetics ; developmental disorders ; ectopic enhancer-promoter interactions ; Gene expression ; gene misregulation ; Genome, Human - genetics ; Genomics ; Hi-C ; Humans ; Molecular Conformation ; neo-TAD ; Segmental Duplications, Genomic - genetics ; SOX9 Transcription Factor - genetics ; topologically associating domains ; Translocation, Genetic - genetics
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 4
    Language: English
    In: American journal of medical genetics. Part A, 2016-09, Vol.170A (9), p.2274-2281
    Description: We describe two siblings who were affected with early onset focal seizures, severe progressive postnatal microcephaly, muscular hypertonia, feeding problems and bouts of apnea, only minimal psychomotor development, as well as death in infancy and childhood. We identified compound heterozygous mutations in BRAT1 exons 5 (c.638_639insA) and 8 (c.1134+1G〉A) in one affected child via next‐generation sequencing of the disease‐associated genome followed by phenotype‐driven bioinformatic analysis. Sanger sequencing confirmed the presence of these mutations in both patients and a heterozygote status of the parents. Whereas the frameshift mutation (c.638_639insA) has been described in one family, the splice‐site mutation (c.1134+1G〉A) is novel. In contrast to all cases published so far, one of our patients showed a considerably milder clinical course with survival into childhood. Investigation of a skeletal muscle biopsy showed a severely reduced COX enzyme histochemical staining, indicating mitochondrial dysfunction. Our data expand the clinical and mutational spectrum of the BRAT1‐associated phenotype. © 2016 Wiley Periodicals, Inc.
    Subject(s): Alleles ; Amino Acid Substitution ; Analysis ; apnea ; Brain - pathology ; BRAT1 ; Child ; Child, Preschool ; Comparative Genomic Hybridization ; Computational Biology - methods ; DNA Mutational Analysis ; Electroencephalography ; Enzymes ; Epilepsy - diagnosis ; Epilepsy - genetics ; Gene Expression ; Genetic aspects ; Genetic Association Studies ; Genomics ; Genotype ; Humans ; Magnetic Resonance Imaging - methods ; Male ; Mitochondria - genetics ; Mitochondria - metabolism ; Muscle, Skeletal - metabolism ; Muscle, Skeletal - pathology ; Muscles ; muscular hypertonia ; Mutation ; Nuclear Proteins - genetics ; Phenotype ; Prostaglandin-Endoperoxide Synthases - metabolism ; Rankings ; seizures ; Seizures (Medicine) ; Ultrasonography
    ISSN: 1552-4825
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Wiley Online Library All Journals
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  • 5
    Language: English
    In: Journal of medical genetics, 2021-06-18, Vol.59 (7), p.662-668
    Description: BackgroundGenes implicated in the Golgi and endosomal trafficking machinery are crucial for brain development, and mutations in them are particularly associated with postnatal microcephaly (POM).MethodsExome sequencing was performed in three affected individuals from two unrelated consanguineous families presenting with delayed neurodevelopment, intellectual disability of variable degree, POM and failure to thrive. Patient-derived fibroblasts were tested for functional effects of the variants.ResultsWe detected homozygous truncating variants in ATP9A. While the variant in family A is predicted to result in an early premature termination codon, the variant in family B affects a canonical splice site. Both variants lead to a substantial reduction of ATP9A mRNA expression. It has been shown previously that ATP9A localises to early and recycling endosomes, whereas its depletion leads to altered gene expression of components from this compartment. Consistent with previous findings, we also observed overexpression of ARPC3 and SNX3, genes strongly interacting with ATP9A.ConclusionIn aggregate, our findings show that pathogenic variants in ATP9A cause a novel autosomal recessive neurodevelopmental disorder with POM. While the physiological function of endogenous ATP9A is still largely elusive, our results underline a crucial role of this gene in endosomal transport in brain tissue.
    Subject(s): Endosomes ; Failure to thrive ; Fibroblasts ; Gene expression ; Genomes ; Genomics ; Genotype & phenotype ; Golgi apparatus ; Hereditary diseases ; Intellectual disabilities ; Microcephaly ; Microencephaly ; Mutation ; Neurodevelopment ; Neurodevelopmental disorders ; Nonsense mutation ; Protein turnover ; Proteins
    ISSN: 0022-2593
    E-ISSN: 1468-6244
    Source: Hellenic Academic Libraries Link
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  • 6
    Language: English
    In: American journal of human genetics, 2014-12-04, Vol.95 (6), p.763-770
    Description: Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A〉G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs∗22), c.298G〉T (p.Ala100Ser), c.294T〉G (p.Phe98Leu), c.269A〉G (p.Glu90Gly), and c.700T〉C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G〉T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism.
    Subject(s): Adolescent ; Adult ; Amino Acid Sequence ; Amino acids ; Causes of ; Child, Preschool ; Exome - genetics ; Female ; Gene mutations ; Genetic disorders ; Genetic research ; Hand Deformities, Congenital - enzymology ; Hand Deformities, Congenital - genetics ; Haplotypes ; Heterozygote ; Homozygote ; Humans ; Infant ; Male ; Metabolism ; Middle Aged ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Oxidoreductases - genetics ; Oxidoreductases - metabolism ; Pedigree ; Pierre Robin Syndrome - enzymology ; Pierre Robin Syndrome - genetics ; Report ; Sequence Alignment ; Sequence Analysis, DNA ; Young Adult
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 7
    Language: English
    In: Journal of investigative dermatology, 2015-10, Vol.135 (10), p.2368-2376
    Description: Gerodermia osteodysplastica is a hereditary segmental progeroid disorder affecting skin, connective tissues, and bone that is caused by loss-of-function mutations in GORAB. The golgin, RAB6-interacting (GORAB) protein localizes to the Golgi apparatus and interacts with the small GTPase RAB6. In this study, we used different approaches to shed more light on the recruitment of GORAB to this compartment. We show that GORAB best colocalizes with trans-Golgi markers and is rapidly displaced upon Brefeldin A exposition, indicating a loose association with Golgi membranes. A yeast two-hybrid screening revealed a specific interaction with the small GTPase ADP-ribosylation factor (ARF5) in its active, GTP-bound form. ARF5 and RAB6 bind to GORAB via the same internal Golgi-targeting RAB6 and ARF5 binding (IGRAB) domain. Two GORAB missense mutations identified in gerodermia osteodysplastica patients fall within this IGRAB domain. GORAB carrying the mutation p.Ala220Pro had a cytoplasmic distribution and failed to interact with both RAB6 and ARF5. In contrast, the p.Ser175Phe mutation displaced GORAB from the Golgi compartment to vesicular structures and selectively impaired ARF5 binding. Our findings indicate that the IGRAB domain is crucial for the Golgi localization of GORAB and that loss of this localization impairs its physiological function.
    Subject(s): ADP-Ribosylation Factors - genetics ; Bone Diseases - congenital ; Bone Diseases - genetics ; Bone Diseases - physiopathology ; Cells, Cultured ; Dwarfism - genetics ; Dwarfism - physiopathology ; Fibroblasts - metabolism ; Golgi Apparatus - metabolism ; HeLa Cells - metabolism ; Humans ; Mutation, Missense ; Protein Binding - genetics ; rab GTP-Binding Proteins - genetics ; Sensitivity and Specificity ; Skin Diseases, Genetic - genetics ; Skin Diseases, Genetic - physiopathology ; Transfection
    ISSN: 0022-202X
    E-ISSN: 1523-1747
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: Journal of inherited metabolic disease, 2021-07, Vol.44 (4), p.972-986
    Description: Several inborn errors of metabolism show cutis laxa as a highly recognizable feature. One group of these metabolic cutis laxa conditions is autosomal recessive cutis laxa type 2 caused by defects in v‐ATPase components or the mitochondrial proline cycle. Besides cutis laxa, muscular hypotonia and cardiac abnormalities are hallmarks of autosomal recessive cutis laxa type 2D (ARCL2D) due to pathogenic variants in ATP6V1A encoding subunit A of the v‐ATPase. Here, we report on three affected individuals from two families with ARCL2D in whom we performed whole exome and Sanger sequencing. We performed functional studies in fibroblasts from one individual, summarized all known probands' clinical, molecular, and biochemical features and compared them, also to other metabolic forms of cutis laxa. We identified novel missense and the first nonsense variant strongly affecting ATP6V1A expression. All six ARCL2D affected individuals show equally severe cutis laxa and dysmorphism at birth. While for one no information was available, two died in infancy and three are now adolescents with mild or absent intellectual disability. Muscular weakness, ptosis, contractures, and elevated muscle enzymes indicated a persistent myopathy. In cellular studies, a fragmented Golgi compartment, a delayed Brefeldin A‐induced retrograde transport and glycosylation abnormalities were present in fibroblasts from two individuals. This is the second and confirmatory report on pathogenic variants in ATP6V1A as the cause of this extremely rare condition and the first to describe a nonsense allele. Our data highlight the tremendous clinical variability of ATP6V1A related phenotypes even within the same family.
    Subject(s): Adenosine triphosphatase ; Adolescent ; Alleles ; ATP6V1A ; autosomal recessive cutis laxa ; Brefeldin A ; Case-Control Studies ; Cutis Laxa - genetics ; Fibroblasts ; Fibroblasts - metabolism ; Glycosylation ; Golgi apparatus ; Golgi Apparatus - metabolism ; Humans ; hypotonia ; Inborn errors of metabolism ; Infant ; Infant, Newborn ; Intellectual disabilities ; Intellectual Disability - genetics ; Male ; Metabolism ; Mitochondria ; Mutation, Missense ; Myopathy ; Pedigree ; Phenotype ; Phenotypes ; progeroid features ; Proline ; Retrograde transport ; Skin ; Vacuolar Proton-Translocating ATPases - genetics ; v‐ATPase
    ISSN: 0141-8955
    E-ISSN: 1573-2665
    Source: Wiley Online Library All Journals
    Source: Get It Now
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  • 9
    Language: English
    In: Human genetics, 2021-08-26, Vol.140 (10), p.1459-1469
    Description: During human organogenesis, lung development is a timely and tightly regulated developmental process under the control of a large number of signaling molecules. Understanding how genetic variants can disturb normal lung development causing different lung malformations is a major goal for dissecting molecular mechanisms during embryogenesis. Here, through exome sequencing (ES), array CGH, genome sequencing (GS) and Hi-C, we aimed at elucidating the molecular basis of bilateral isolated lung agenesis in three fetuses born to a non-consanguineous family. We detected a complex genomic rearrangement containing duplicated, triplicated and deleted fragments involving the SHH locus in fetuses presenting complete agenesis of both lungs and near-complete agenesis of the trachea, diagnosed by ultrasound screening and confirmed at autopsy following termination. The rearrangement did not include SHH itself, but several regulatory elements for lung development, such as MACS1, a major SHH lung enhancer, and the neighboring genes MNX1 and NOM1 . The rearrangement incorporated parts of two topologically associating domains (TADs) including their boundaries. Hi-C of cells from one of the affected fetuses showed the formation of two novel TADs each containing SHH enhancers and the MNX1 and NOM1 genes. Hi-C together with GS indicate that the new 3D conformation is likely causative for this condition by an inappropriate activation of MNX1 included in the neo-TADs by MACS1 enhancer, further highlighting the importance of the 3D chromatin conformation in human disease.
    Subject(s): Abnormalities, Multiple - genetics ; Adult ; Agenesis ; Autopsy ; Biomedical and Life Sciences ; Biomedicine ; Cadaver ; Chromatin ; Conformation ; Cytogenetics ; Developmental biology ; Embryogenesis ; Enhancers ; Evolution, Molecular ; Female ; Fetus ; Fetuses ; Gene Function ; Genes ; Genetic variance ; Genetic Variation ; Genome, Human ; Genomes ; Genomics ; Human Genetics ; Humans ; Lung - abnormalities ; Lung - growth & development ; Lung - ultrastructure ; Lung Diseases - genetics ; Lungs ; Male ; Metabolic Diseases ; Molecular Medicine ; Molecular modelling ; Organogenesis ; Organogenesis - genetics ; Original Investigation ; Pregnancy ; Regulatory sequences ; Trachea
    ISSN: 0340-6717
    E-ISSN: 1432-1203
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: American journal of medical genetics. Part A, 2016-04, Vol.170A (4), p.1080-1085
    Description: Osteogenesis imperfecta (OI) and Ehlers–Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006‐1G 〉 A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin‐X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype. © 2016 Wiley Periodicals, Inc.
    Subject(s): Alleles ; Analysis ; Biopsy ; COL1A1 ; Collagen ; Collagen (type I) ; Collagen Type I - genetics ; Collagen Type I - metabolism ; DNA Mutational Analysis ; Ehlers-Danlos syndrome ; Ehlers-Danlos Syndrome - diagnosis ; Ehlers-Danlos Syndrome - genetics ; Exome ; Extracellular matrix ; Fibroblasts ; Fractures ; Genetic aspects ; Genetic disorders ; Heterozygote ; High-Throughput Nucleotide Sequencing ; Humans ; Immunohistochemistry ; Infant ; Male ; Mutation ; Osteogenesis ; Osteogenesis imperfecta ; Osteogenesis Imperfecta - diagnosis ; Osteogenesis Imperfecta - genetics ; Pedigree ; Phenotype ; Skin ; Tenascin ; Tenascin - genetics ; TNXB ; whole exome sequencing
    ISSN: 1552-4825
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Wiley Online Library All Journals
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