11,046 results match your criteria Human molecular genetics[Journal]


Bioenergetic deficits in Huntington's disease iPSC-derived neural cells and rescue with glycolytic metabolites.

Hum Mol Genet 2019 Feb 15. Epub 2019 Feb 15.

Division of Neurobiology, Departments of Psychiatry, Neurology, Pharmacology, and Neuroscience, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, Maryland 21287 USA.

Altered cellular metabolism is believed to be an important contributor to pathogenesis of the neurodegenerative disorder Huntington's disease (HD). Research has primarily focused on mitochondrial toxicity, which can cause death of the vulnerable striatal neurons, but other aspects of metabolism have also been implicated. Most previous studies have been carried out using post-mortem human brain or non-human cells. Read More

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http://dx.doi.org/10.1093/hmg/ddy430DOI Listing
February 2019
1 Read

Disturbed Neurotransmitter Homeostasis in Ether Lipid Deficiency.

Hum Mol Genet 2019 Feb 13. Epub 2019 Feb 13.

Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria.

Plasmalogens, the most prominent ether (phospho)lipids in mammals, are structural components of most cellular membranes. Due to their physicochemical properties and abundance in the central nervous system, a role of plasmalogens in neurotransmission has been proposed, but conclusive data are lacking. Here, we targeted this issue in the glyceronephosphate O-acyltransferase (Gnpat) KO mouse, a model of complete deficiency in ether lipid biosynthesis. Read More

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http://dx.doi.org/10.1093/hmg/ddz040DOI Listing
February 2019
1 Read

Mineralocorticoid Receptor Antagonists Improve Membrane Integrity Independent of Muscle Force in Muscular Dystrophy.

Hum Mol Genet 2019 Feb 13. Epub 2019 Feb 13.

Department of Physiology and Cell Biology.

Mineralocorticoid receptor (MR) drugs have been used clinically for decades to treat cardiovascular diseases. MR antagonists show preclinical efficacy not only for heart in Duchenne muscular dystrophy models, but also improve skeletal muscle force and muscle membrane integrity. The mechanisms of action of MR antagonists in skeletal muscles are entirely unknown. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddz039DOI Listing
February 2019
1 Read

Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson's iPSC-derived dopamine neurons.

Hum Mol Genet 2019 Feb 11. Epub 2019 Feb 11.

The Oxford Parkinson's Disease Centre, University of Oxford, Oxford UK.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and a central role for α-Synuclein (αSyn; SNCA) in disease aetiology has been proposed based on genetics and neuropathology. To better understand the pathological mechanisms of αSyn, we generated induced pluripotent stem cells (iPSCs) from healthy individuals and PD patients carrying the A53T SNCA mutation or a triplication of the SNCA locus and differentiated them into dopaminergic neurons (DAn). iPSC-derived DAn from PD patients carrying either mutation showed increased intracellular αSyn accumulation, and DAn from patients carrying the SNCA triplication displayed oligomeric αSyn pathology and elevated αSyn extracellular release. Read More

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http://dx.doi.org/10.1093/hmg/ddz038DOI Listing
February 2019
6.393 Impact Factor

HDAC Inhibitors Rescue Multiple Disease-Causing CFTR Variants.

Hum Mol Genet 2019 Feb 7. Epub 2019 Feb 7.

Scripps Research, Department of Molecular Medicine.

Understanding the role of the epigenome in protein misfolding diseases remains a challenge in light of genetic diversity found in the world-wide population revealed by human genome sequencing efforts and the highly variable response of the disease population to therapeutics. An ever-growing body of evidence has shown that histone deacetylase (HDAC) inhibitors (HDACi) can have significant benefit in correcting protein misfolding diseases that occur in response to both familial and somatic mutation. Cystic fibrosis (CF) is a familial autosomal recessive disease, caused by genetic diversity in the CF transmembrane conductance regulator (CFTR) gene, a cAMP-dependent chloride channel expressed at the apical plasma membrane of epithelial cells in multiple tissues. Read More

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http://dx.doi.org/10.1093/hmg/ddz026DOI Listing
February 2019
1 Read

Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease.

Hum Mol Genet 2019 Feb 12. Epub 2019 Feb 12.

Department of Neuroscience.

An early hallmark of Alzheimer's disease is the accumulation of amyloid-β, inspiring numerous therapeutic strategies targeting this peptide. An alternative approach is to destabilize the amyloid precursor protein (APP) from which Aβ is derived. We interrogated innate pathways governing APP stability using a siRNA screen for modifiers whose own reduction diminished APP in human cell lines and transgenic Drosophila. Read More

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http://dx.doi.org/10.1093/hmg/ddz034DOI Listing
February 2019

Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle.

Hum Mol Genet 2019 Feb 11. Epub 2019 Feb 11.

Light Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.

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http://dx.doi.org/10.1093/hmg/ddz035DOI Listing
February 2019

Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.

Hum Mol Genet 2019 Feb 1. Epub 2019 Feb 1.

Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, Cranmer Terrace, London, UK.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here we show that mutations in KLHL24 cause hypertrophic cardiomyopathy in humans. Using genome-wide linkage analysis and exome sequencing we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Read More

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http://dx.doi.org/10.1093/hmg/ddz032DOI Listing
February 2019
1 Read
6.393 Impact Factor

Titin truncations lead to impaired cardiomyocyte autophagy and mitochondrial function in vivo.

Hum Mol Genet 2019 Feb 4. Epub 2019 Feb 4.

Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore, Singapore 169857, Singapore.

Titin-truncating variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM). TTNtv occur in ~1% of the general population and causes subclinical cardiac remodeling in asymptomatic carriers. In rat models with either proximal or distal TTNtv, we previously showed altered cardiac metabolism at baseline and impaired cardiac function in response to stress. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddz033DOI Listing
February 2019
2 Reads

Neuroprotective effects of PACAP against paraquat-induced oxidative stress in the Drosophila central nervous system.

Hum Mol Genet 2019 Jan 30. Epub 2019 Jan 30.

Genes Circuits Rhythms and Neuropathology (GCRN) Group, Brain Plasticity Unit, CNRS, ESPCI Paris, Labex Memolife, PSL Research University, 10 rue Vauquelin, 75005 Paris, France.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that can arise after long-term exposure to environmental oxidative stressors, such as the herbicide paraquat (PQ). Here we investigated the potential neuroprotective action of vertebrate pituitary adenylate cyclase-activating polypeptide (PACAP) against PQ in Drosophila. We found that pretreatment with this neuropeptide applied to the ventral nerve cord (VNC) at low doses markedly extended the survival of wild-type decapitated flies exposed to neurotoxic levels of PQ or dopamine (DA). Read More

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http://dx.doi.org/10.1093/hmg/ddz031DOI Listing
January 2019

UBE3A regulates the transcription of IRF, an anti-viral immunity.

Hum Mol Genet 2019 Jan 26. Epub 2019 Jan 26.

RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.

UBE3A is a gene responsible for the pathogenesis of Angelman syndrome (AS), a neurodevelopmental disorder characterized by symptoms such as intellectual disability, delayed development and severe speech impairment. UBE3A encodes an E3 ubiquitin ligase, for which several targets have been identified, including synaptic molecules. Although proteolysis mainly occurs in the cytoplasm, UBE3A is localized to the cytoplasm and the nucleus. Read More

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http://dx.doi.org/10.1093/hmg/ddz019DOI Listing
January 2019

Deleting nebulin's C-terminus reveals its importance to sarcomeric structure and function and is sufficient to invoke nemaline myopathy.

Hum Mol Genet 2019 Jan 24. Epub 2019 Jan 24.

Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, 85721, USA.

Nebulin is a large skeletal muscle protein wound around the thin filaments, with its C-terminus embedded within the Z-disk and its N-terminus extending out towards the thin filament pointed end. While nebulin's C-terminus has been implicated in both sarcomeric structure and function as well as the development of nemaline myopathy, the contributions of this region remain largely unknown. Additionally, the C-terminus is reported to contribute to muscle hypertrophy via the IGF-1 growth pathway. Read More

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http://dx.doi.org/10.1093/hmg/ddz016DOI Listing
January 2019

CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection.

Hum Mol Genet 2019 Jan 26. Epub 2019 Jan 26.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China.

High myopia is a severe form of nearsightedness, which can result in blindness due to its associated complications. While both genetic and environmental factors can cause high myopia, early-onset high myopia (eoHM), which is defined as high myopia that occurs before school age, is considered to be caused mainly by genetic variations, with minimal environmental involvement. Here, we report six rare heterozygous loss-of-function (LoF) variants in CPSF1 that were identified in six of 623 probands with eoHM but none of 2657 probands with other forms of genetic eye diseases; this difference was statistically significant (P = 4. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddz029DOI Listing
January 2019
3 Reads

Quantitative reduction of RyR1 protein caused by a single-allele frameshift mutation in RYR1 ex36 impairs the strength of adult skeletal muscle fibres.

Hum Mol Genet 2019 Jan 25. Epub 2019 Jan 25.

Departments of Anaesthesia and Biomedicine, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.

Here we characterized a mouse model knocked-in for a frameshift mutation in RYR1 exon 36 (p.Gln1970fsX16) that is isogenic to that identified in one parent of a severely affected patient with recessively inherited Multiminicore disease. This individual carrying the RYR1 frameshifting mutation complained of mild muscle weakness and fatigability. Read More

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http://dx.doi.org/10.1093/hmg/ddz025DOI Listing
January 2019
1 Read

Systemic investigation of bone and muscle abnormalities in dystrophin/utrophin double knockout mice during postnatal development and the mechanisms.

Hum Mol Genet 2019 Jan 28. Epub 2019 Jan 28.

Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX.

The dystrophin-/-/utrophin-/- double knockout (dKO-Hom) mouse is a murine model of human Duchenne muscular dystrophy (DMD). This study investigated the bone and muscle abnormalities of dKO-Hom mouse and mechanisms. We collected bone and skeletal muscle samples from control mice and three muscular dystrophic mouse models at different ages, and performed MicroCT and histological analyses of both bone and skeletal muscle tissues. Read More

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http://dx.doi.org/10.1093/hmg/ddz012DOI Listing
January 2019
1 Read

GBA haploinsufficiency accelerates alpha synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson's disease=.

Hum Mol Genet 2019 Jan 28. Epub 2019 Jan 28.

Department of Neurology Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

Parkinson's disease (PD) is characterized by dopaminergic cell loss and the accumulation of pathological alpha synuclein (asyn), but its precise pathomechanism remains unclear, and no appropriate animal model has yet been established. Recent studies have shown that a heterozygous mutation of glucocerebrosidase (gba) is one of the most important genetic risk factors in PD. To create mouse model for PD, we crossed asyn Bacterial Artificial Chromosome transgenic mice with gba heterozygous knockout mice. Read More

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http://dx.doi.org/10.1093/hmg/ddz030DOI Listing
January 2019

The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation.

Hum Mol Genet 2019 Jan 25. Epub 2019 Jan 25.

Departments of Biochemistry and Molecular Biology.

Mutations in IRF6, TFAP2A and GRHL3 cause orofacial clefting syndromes in humans. However, Tfap2a and Grhl3 are also required for neurulation in mice. Here, we found that homeostasis of Irf6 is also required for development of the neural tube and associated structures. Read More

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http://dx.doi.org/10.1093/hmg/ddz010DOI Listing
January 2019
1 Read

Nonsense-mediated mRNA decay efficiency varies in choroideremia providing a target to boost small molecule therapeutics.

Hum Mol Genet 2019 Jan 23. Epub 2019 Jan 23.

Development, Ageing and Disease, UCL Institute of Ophthalmology, London, EC1V 9EL, UK.

Choroideremia (CHM) is an x-linked recessive chorioretinal dystrophy, with 30% caused by nonsense mutations in the CHM gene resulting in an in-frame premature termination codon (PTC). Nonsense mediated decay (NMD) is the cell's natural surveillance mechanism, that detects and destroys PTC containing transcripts, with UPF1 being the central NMD modulator. NMD efficiency can be variable amongst individuals with some transcripts escaping destruction, leading to the production of a truncated non-functional or partially functional protein. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddz028DOI Listing
January 2019
3 Reads

Novel germline STK11 variants and breast cancer phenotype identified in an Indian cohort of Peutz-Jeghers syndrome.

Hum Mol Genet 2019 Jan 25. Epub 2019 Jan 25.

Sarin Lab, Advanced Centre for Treatment Research and Education in Cancer-Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, Maharashtra, India.

Peutz-Jeghers syndrome (PJS) caused by germline STK11 variants is a rare autosomal dominant cancer predisposition syndrome characterized by multiple gastrointestinal (GI) hamartomatous polyps, mucocutaneous pigmentation and a high inherited risk of developing GI, breast and other cancers. Despite GI and breast being the two most common PJS associated cancer sites, the immunohistochemical (IHC) and molecular features of these tumours in carriers of STK11 variant is not known. Detailed phenotyping including tumour IHC and its correlation with comprehensive STK11 genotyping by full gene sequencing followed by large genomic rearrangement analysis was performed in an Indian PJS cohort. Read More

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http://dx.doi.org/10.1093/hmg/ddz027DOI Listing
January 2019
1 Read

Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease.

Hum Mol Genet 2019 Jan 22. Epub 2019 Jan 22.

Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Cysteamine bitartrate is an FDA-approved therapy for nephropathic cystinosis postulated to enhance glutathione biosynthesis. We hypothesized this antioxidant effect may reduce oxidative stress in primary mitochondrial respiratory chain (RC) disease, improving cellular viability and organismal health. Here, we systematically evaluated the therapeutic potential of cysteamine bitartrate in RC disease models spanning three evolutionary species. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddz023DOI Listing
January 2019
4 Reads

Nearly complete deletion of BubR1 causes microcephaly through shortened mitosis and massive cell death.

Hum Mol Genet 2019 Jan 22. Epub 2019 Jan 22.

Shriners Hospitals Pediatric Research Center, Department of Anatomy and Cell Biology, Lewis Katz School of Medicine Temple University, Philadelphia, PA, USA.

BubR1 encoded by BUB1B is a crucial mitotic checkpoint protein ensuring proper segregation of chromosomes during mitosis. Mutations of BUB1B are responsible for mosaic variegated aneuploidy (MVA), a human congenital disorder characterized by extensive abnormalities in chromosome number. Although microcephaly is a prominent feature of MVA carrying the BUB1B mutation, how BubR1 deficiency disturbs neural progenitor proliferation and neuronal output and leads to microcephaly is unknown. Read More

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http://fdslive.oup.com/www.oup.com/pdf/production_in_progres
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http://dx.doi.org/10.1093/hmg/ddz022DOI Listing
January 2019
11 Reads

Bi-allelic AEBP1 mutations in two patients with Ehlers-Danlos syndrome.

Hum Mol Genet 2019 Jan 22. Epub 2019 Jan 22.

Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University Hospital, 9000 Ghent, Belgium.

The Ehlers-Danlos syndromes (EDS) are a clinically and molecularly diverse group of heritable connective tissue disorders caused by defects in a wide range of genes. Recently, biallelic loss-of-function mutations in the AEBP1 gene were reported in three families with an autosomal recessive EDS-like condition characterized by thin and hyperextensible skin, poor wound healing with prominent atrophic scarring, joint hypermobility and osteoporosis. Using whole exome sequencing, we identified novel bi-allelic AEBP1 variants in two unrelated adult patients, previously diagnosed with an undefined EDS type which shows important clinical resemblance to several other EDS subtypes. Read More

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http://dx.doi.org/10.1093/hmg/ddz024DOI Listing
January 2019

A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta.

Hum Mol Genet 2019 Jan 16. Epub 2019 Jan 16.

Center for Medical Genetics Ghent, Ghent University Hospital, Department of Biomolecular Medicine, Ghent 9000, Belgium.

The cyclic adenosine monophosphate (AMP) responsive element binding protein 3-like 1 (CREB3L1) gene codes for the endoplasmic reticulum stress transducer old astrocyte specifically induced substance (OASIS), which has an important role in osteoblast differentiation during bone development. Deficiency of OASIS is linked to a severe form of autosomal recessive osteogenesis imperfecta (OI), but only few patients have been reported. We identified the first homozygous pathogenic missense variant (p. Read More

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http://dx.doi.org/10.1093/hmg/ddz017DOI Listing
January 2019

A study in scarlet: MC1R as the main predictor of red hair and exemplar of the flip-flop effect.

Hum Mol Genet 2019 Jan 16. Epub 2019 Jan 16.

McGill University, Anesthesia and the Alan Edwards Centre for Research on Pain, Montreal, QC, Canada.

Genetic variation in melanocortin-1 receptor (MC1R) is a known contributor to disease-free red hair in humans. Three loss-of-function single-nucleotide variants (rs1805007, rs1805008, and rs1805009) have been established as strongly correlated with red hair. The contribution of other loss-of-function MC1R variants (in particular rs1805005, rs2228479, and rs885479) and the extent to which other genetic loci are involved in red hair colour is less well understood. Read More

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http://dx.doi.org/10.1093/hmg/ddz018DOI Listing
January 2019
1 Read

Evolutionary redesign of the lysosomal enzyme arylsulfatase A increases efficacy of enzyme replacement therapy for metachromatic leukodystrophy.

Hum Mol Genet 2019 Jan 18. Epub 2019 Jan 18.

Institute of Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms University, D-53115 Bonn, Germany.

Protein-engineering is a means to optimize protein therapeutics developed for the treatment of so far incurable diseases including cancers and genetic disorders. Here we report on an engineering approach in which we successfully increased the catalytic rate constant of an enzyme that is presently evaluated in enzyme replacement therapies (ERT) of a lysosomal storage disease (LSD). Although ERT is a treatment option for many LSDs, outcomes are lagging far behind expectations for most of them. Read More

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http://dx.doi.org/10.1093/hmg/ddz020DOI Listing
January 2019

MFN2 mutations in Charcot-Marie-Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics.

Hum Mol Genet 2019 Jan 11. Epub 2019 Jan 11.

Biology.

Charcot-Marie-Tooth disease (CMT) type 2A is an axonal form of peripheral neuropathy, due almost exclusively to dominant mutations in the nuclear gene encoding the mitochondrial protein mitofusin-2 (MFN2). However, there is no understanding of the relationship of clinical phenotype to genotype. MFN2 has two functions: it promotes inter-mitochondrial fusion and mediates ER-mitochondrial tethering at mitochondria-associated ER membranes (MAM). Read More

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http://dx.doi.org/10.1093/hmg/ddz008DOI Listing
January 2019
2 Reads

Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy.

Hum Mol Genet 2019 Jan 14. Epub 2019 Jan 14.

Sorbonne Université, INSERM, Association Institut de Myologie, Centre de Recherche en Myologie, UMRS974, 47 bd de l'Hôpital, 75013 Paris, France.

Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease leading to ptosis, dysphagia, and proximal limb muscles at later stages. A short abnormal (GCN) triplet expansion in the polyA-binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. Here we demonstrate that treating mice with guanabenz acetate (GA), an FDA-approved antihypertensive drug, reduces the size and number of nuclear aggregates, improves muscle force, protects myofibers from the pathology-derived turnover and decreases fibrosis. Read More

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http://dx.doi.org/10.1093/hmg/ddz007DOI Listing
January 2019
1 Read

Multifaceted Hoxa13 function in urogenital development underlies the Hand-Foot-Genital Syndrome.

Hum Mol Genet 2019 Jan 10. Epub 2019 Jan 10.

Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada.

Hand-Foot-Genital syndrome is a rare condition caused by mutations in the HOXA13 gene and characterized by limb malformations and urogenital defects. While the role of Hoxa13 in limb development has been extensively studied, its function during the development of the urogenital system remains elusive mostly due to the embryonic lethality of Hoxa13 homozygous mutant mice. Using a conditional inactivation strategy, we show that mouse fetuses lacking Hoxa13 function develop megaureters, hydronephrosis and malformations of the uterus, reminiscent of the defects characterizing patients with Hand-Foot-Genital syndrome. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddz013DOI Listing
January 2019
3 Reads

Cbs overdosage is necessary and sufficient to induce cognitive phenotypes in mouse models of Down syndrome and interacts genetically with Dyrk1a.

Hum Mol Genet 2019 Jan 10. Epub 2019 Jan 10.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, 1 rue Laurent Fries, 67404 Illkirch, France.

Identifying dosage-sensitive genes is a key to understand the mechanisms underlying intellectual disability in Down syndrome (DS). The Dp(17Abcg1-Cbs)1Yah DS mouse model (Dp1Yah) shows cognitive phenotypes that need to be investigated to identify the main genetic driver. Here, we report that three copies of the cystathionine-beta-synthase gene (Cbs) in the Dp1Yah mice are necessary to observe a deficit in the novel object recognition (NOR) paradigm. Read More

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http://dx.doi.org/10.1093/hmg/ddy447DOI Listing
January 2019
1 Read

Sex differences in gene expression in response to ischemia in the human left ventricular myocardium.

Hum Mol Genet 2019 Jan 14. Epub 2019 Jan 14.

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School. Boston, MA 02115, USA.

Sex differences exist in the prevalence, presentation, and outcomes of ischemic heart disease (IHD). Females have higher risk of heart failure post myocardial infarction relative to males, and are 2-3 times more likely to die after CABG surgery. We examined sex differences in human myocardial gene expression in response to ischemia. Read More

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http://dx.doi.org/10.1093/hmg/ddz014DOI Listing
January 2019
1 Read

Genome-wide association study of anti-Müllerian hormone levels in pre-menopausal women of late reproductive age and relationship with genetic determinants of reproductive lifespan.

Hum Mol Genet 2019 Jan 14. Epub 2019 Jan 14.

Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. Read More

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http://dx.doi.org/10.1093/hmg/ddz015DOI Listing
January 2019
1 Read

Discovery of mitochondrial DNA variants associated with genome-wide blood cell gene expression: a population-based mtDNA sequencing study.

Hum Mol Genet 2019 Jan 9. Epub 2019 Jan 9.

Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Background: The effect of mitochondrial DNA variation on peripheral blood transcriptomics in health and disease is not fully known. Sex-specific mitochondrially controlled gene expression patterns have been shown in Drosophila melanogaster but in humans, evidence is lacking. Functional variation in mitochondrial DNA may also have a role in the development of type 2 diabetes and its precursor state, i. Read More

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http://dx.doi.org/10.1093/hmg/ddz011DOI Listing
January 2019
1 Read

LRRK2 impairs PINK1/Parkin-dependent mitophagy via its kinase activity: pathologic insights into Parkinson's disease.

Hum Mol Genet 2019 Jan 9. Epub 2019 Jan 9.

Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.

Mutations of LRRK2, encoding leucine-rich repeat kinase 2, are the leading cause of autosomal dominant Parkinson's disease (PD). The most frequent of these mutations, G2019S substitution, increases kinase activity, but it remains unclear how it causes PD. Recent studies suggest that LRRK2 modulates mitochondrial homeostasis. Read More

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http://dx.doi.org/10.1093/hmg/ddz004DOI Listing
January 2019
1 Read

Mutant huntingtin expression in microglia is neither required nor sufficient to cause the Huntington's disease-like phenotype in BACHD mice.

Hum Mol Genet 2019 Jan 9. Epub 2019 Jan 9.

Centre for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children's and Women's Hospital, 980 West 28 th Avenue, Vancouver, BC, Canada V5Z 4H4.

Huntington's disease (HD), is caused by a CAG repeat expansion in the HTT gene, and is characterized by early and selective striatal neurodegeneration. The huntingtin (HTT) protein is ubiquitously expressed in many tissues and the cellular pathogenesis of the disease is not fully understood. Immune cell dysfunction due to mutant HTT (mHTT) expression and aberrant immune system activation in HD patients suggests that inflammatory processes may contribute to HD pathogenesis. Read More

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http://dx.doi.org/10.1093/hmg/ddz009DOI Listing
January 2019
5 Reads

A Neurodevelopmental Disorder Caused by Mutations in the VPS51 Subunit of the GARP and EARP Complexes.

Hum Mol Genet 2019 Jan 8. Epub 2019 Jan 8.

Greenwood Genetic Center, Greenwood, South Carolina, USA.

GARP and EARP are related heterotetrameric protein complexes that associate with the cytosolic face of the trans-Golgi network and recycling endosomes, respectively. At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments. GARP and EARP share three subunits, VPS51, VPS52 and VPS53, and each has an additional complex-specific subunit, VPS54 or VPS50, respectively. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddy423DOI Listing
January 2019
7 Reads

Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations.

Hum Mol Genet 2019 Jan 8. Epub 2019 Jan 8.

Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain.

Mutations in MORC2 lead to an axonal form of Charcot-Marie-Tooth (CMT) neuropathy type 2Z. To date, thirty-one families have been described with mutations in MORC2, indicating that this gene is frequently involved in axonal CMT cases. While the genetic data clearly establish the causative role of MORC2 in CMT2Z, the impact of its mutations on neuronal biology and their phenotypic consequences in patients remains to be clarified. Read More

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http://dx.doi.org/10.1093/hmg/ddz006DOI Listing
January 2019
1 Read

Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample.

Hum Mol Genet 2019 Jan 8. Epub 2019 Jan 8.

Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN.

Interpretation of genetic association results is difficult because signals often lack biological context. To generate hypotheses of the functional genetic etiology of complex cardiometabolic traits, we estimated the genetically determined component of gene expression from common variants using PrediXcan (1) and determined genes with differential predicted expression by trait. PrediXcan imputes tissue-specific expression levels from genetic variation using variant-level effect on gene expression in transcriptome data. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddy435DOI Listing
January 2019
8 Reads

The effect of mutant GBA1 on accumulation and aggregation of α-synuclein.

Hum Mol Genet 2019 Jan 7. Epub 2019 Jan 7.

School of Molecular Cell Biology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel.

Gaucher disease (GD) patients and carriers of GD mutations have a higher propensity to develop Parkinson disease (PD) in comparison to the non-GD population. This implies that mutant GBA1 allele is a predisposing factor for the development of PD. One of the major characteristics of PD is the presence of oligomeric α-synuclein-positive inclusions known as Lewy bodies in the dopaminergic neurons localized to the substantia nigra pars compacta. Read More

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http://dx.doi.org/10.1093/hmg/ddz005DOI Listing
January 2019

Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria.

Hum Mol Genet 2019 Jan 7. Epub 2019 Jan 7.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Acute intermittent porphyria (AIP) is an inborn error of heme biosynthesis due to the deficiency of hydroxymethylbilane synthase (HMBS) activity. Human AIP heterozygotes have episodic acute neurovisceral attacks that typically start after puberty, whereas patients with homozygous dominant AIP (HD-AIP) have early-onset chronic neurological impairment, including ataxia and psychomotor retardation. To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddz003DOI Listing
January 2019
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TIPE2 gene transfer with adeno-associated virus 9 ameliorates dystrophic pathology in mdx mice.

Hum Mol Genet 2019 Jan 4. Epub 2019 Jan 4.

Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, McGovern Medical School, Houston TX 77030, USA.

Duchenne muscle dystrophy (DMD), characterized by progressive loss of muscle architecture and function, is caused by lack of dystrophin expression in the sarcolemma of myofibers. Recurrent muscle damages in DMD patients and DMD mouse model, mdx, lead to chronic inflammation, which further exacerbate the muscle histopathology. It is critical to find a successful therapy that will improve the histopathology of muscles of DMD patients and restore skeletal muscle function. Read More

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http://dx.doi.org/10.1093/hmg/ddz001DOI Listing
January 2019

Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein.

Hum Mol Genet 2019 Jan 4. Epub 2019 Jan 4.

Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Missense mutations in the gene, MAP3K1, are a common cause of 46,XY gonadal dysgenesis, accounting for 15-20% of cases (1). Functional studies demonstrated that all of these mutations cause a protein gain-of-function that alters co-factor binding and increases phosphorylation of the downstream MAP kinase pathway targets, MAPK11, MAP3K, and MAPK1. This dysregulation of the MAP kinase pathway results in increased CTNNB1, increased expression of WNT4 and FOXL2, and decreased expression of SRY and SOX9. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddz002DOI Listing
January 2019
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EAP1 regulation of GnRH promoter activity is important for human pubertal timing.

Hum Mol Genet 2019 Jan 4. Epub 2019 Jan 4.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK, EC1M 6BQ.

The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include Enhanced At Puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. Read More

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http://dx.doi.org/10.1093/hmg/ddy451DOI Listing
January 2019

The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy.

Hum Mol Genet 2019 Jan 2. Epub 2019 Jan 2.

Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, Porter Neuroscience Research Center, National Institutes of Health, Bethesda, MD, USA.

Epilepsy, deafness, onychodystrophy, osteodystrophy and intellectual disability are associated with a spectrum of mutations of human TBC1D24. The mechanisms underlying TBC1D24-associated disorders and the functions of TBC1D24 are not well understood. Using CRISPR-Cas9 genome editing, we engineered a mouse with a premature translation stop codon equivalent to human S324Tfs*3, a recessive mutation of TBC1D24 associated with early infantile epileptic encephalopathy (EIEE). Read More

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http://dx.doi.org/10.1093/hmg/ddy445DOI Listing
January 2019

Contribution of mitochondrial ND1 3394T>C mutation to the phenotypic manifestation of Leber's hereditary optic neuropathy.

Hum Mol Genet 2018 Dec 31. Epub 2018 Dec 31.

Division of Medical Genetics and Genomics, the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Mitochondrial DNA (mtDNA) mutations have been associated with Leber's hereditary optic neuropathy (LHON) and their pathophysiology remains poorly understood. In this study, we investigated the pathophysiology of a LHON susceptibility allele (m.3394T>C, p. Read More

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http://dx.doi.org/10.1093/hmg/ddy450DOI Listing
December 2018
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Tau/MAPT disease-associated variant A152T alters tau function and toxicity via impaired retrograde axonal transport.

Hum Mol Genet 2018 Dec 26. Epub 2018 Dec 26.

Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

Mutations in the microtubule-associated protein tau (MAPT) underlie multiple neurodegenerative disorders, yet the pathophysiological mechanisms are unclear. A novel variant in MAPT resulting in an alanine to threonine substitution at position 152 (A152T tau) has recently been described as a significant risk factor for both frontotemporal lobar degeneration and Alzheimer's disease. Here we use complementary computational, biochemical, molecular, genetic and imaging approaches in Caenorhabditis elegans and mouse models to interrogate the effects of the A152T variant on tau function. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddy442DOI Listing
December 2018
11 Reads

GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich Ataxia cellular models.

Hum Mol Genet 2018 Dec 26. Epub 2018 Dec 26.

Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein crucial for iron-sulphur cluster biogenesis and ATP production. Currently there is no therapy to slow down the progression of FRDA. Recent evidence indicates that posttranslational regulation of residual frataxin levels can rescue some of the functional deficit of FRDA, raising the possibility of enhancing levels of residual frataxin as a treatment for FRDA. Read More

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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddy448DOI Listing
December 2018
7 Reads

Functional characterization of the ZEB2 regulatory landscape.

Hum Mol Genet 2018 12 26. Epub 2018 Dec 26.

Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Zinc finger E-box-binding homeobox 2 (ZEB2) is a key developmental regulator of the central nervous system (CNS). Although the transcriptional regulation of ZEB2 is essential for CNS development, the elements that regulate ZEB2 expression have yet to be identified. Here, we identified a proximal regulatory region of ZEB2 and characterized transcriptional enhancers during neuronal development. Read More

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http://dx.doi.org/10.1093/hmg/ddy440DOI Listing
December 2018

Loss of the dystonia gene Thap1 leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes.

Hum Mol Genet 2018 Dec 26. Epub 2018 Dec 26.

Davee Department of Neurology.

Dystonia is a movement disorder characterized by involuntary and repetitive co-contractions of agonist and antagonist muscles. Dystonia 6 (DYT6) is an autosomal dominant dystonia caused by loss of function mutations in the zinc finger transcription factor THAP1. We have generated Thap1 knock-out mice with a view to understanding its transcriptional role. Read More

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http://dx.doi.org/10.1093/hmg/ddy433DOI Listing
December 2018