11,067 results match your criteria Human molecular genetics[Journal]


Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study.

Hum Mol Genet 2019 Apr 22. Epub 2019 Apr 22.

Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA.

DNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) of high-risk pregnancies. Read More

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http://dx.doi.org/10.1093/hmg/ddz084DOI Listing

Dynll1 is essential for development and promotes endochondral bone formation by regulating intraflagellar Dynein function in primary cilia.

Hum Mol Genet 2019 Apr 22. Epub 2019 Apr 22.

St. Vincent's Institute of Medical Research.

Mutations in subunits of the cilia-specific cytoplasmic Dynein-2 (CD2) complex cause short-rib thoracic dystrophy syndromes (SRTDs), characterized by impaired bone growth and life-threatening perinatal respiratory complications. Different SRTD mutations result in varying disease severities. It remains unresolved whether this reflects the extent of retained hypomorphic protein functions or relative importance of the affected subunits for the activity of the CD2 holoenzyme. Read More

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http://dx.doi.org/10.1093/hmg/ddz083DOI Listing

Targeted Knock-In Mice with a Human Mutation in GRTH/DDX25 Reveals the Essential Role of Phosphorylated GRTH in Spermatid Development during Spermatogenesis.

Hum Mol Genet 2019 Apr 22. Epub 2019 Apr 22.

Section on Molecular Endocrinology, Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) is a testis specific member of the DEAD-box family of RNA helicases expressed in meiotic and haploid germ cells which plays an essential role in spermatogenesis. There are two species of GRTH the 56 kDa non-phospho and 61 kDa phospho forms. Our early studies revealed a missense mutation (R242H) of GRTH in azoospermic men that when expressed in COS1-cells lack the phospho-form of GRTH. 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/ddz079DOI Listing
April 2019
2 Reads

Postnatal Development of Mice with Combined Genetic Depletions of Lamin A/C, Emerin and Lamina-associated Polypeptide 1.

Hum Mol Genet 2019 Apr 22. Epub 2019 Apr 22.

Department of Medicine.

Mutations in LMNA encoding lamin A/C and EMD encoding emerin cause cardiomyopathy and muscular dystrophy. Lmna null mice develop these disorders and have a lifespan of 7-8 weeks. Emd null mice show no overt pathology and have normal skeletal muscle but with regeneration defects. 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/ddz082DOI Listing
April 2019
2 Reads

MBNL1 overexpression is not sufficient to rescue the phenotypes in a mouse model of RNA toxicity.

Hum Mol Genet 2019 Apr 1. Epub 2019 Apr 1.

Department of Pathology, University of Virginia, Charlottesville, VA, USA.

Myotonic dystrophy type 1 (DM1) is caused by an expanded (CTG)n tract in the 3'UTR of the DM protein kinase (DMPK) gene. The RNA transcripts produced from the expanded allele sequester or alter the function of RNA-binding proteins (MBNL1, CUGBP1, etc.). Read More

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http://dx.doi.org/10.1093/hmg/ddz065DOI Listing
April 2019
6.393 Impact Factor

Exploring the cross-phenotype network region of disease modules reveals concordant and discordant pathways between chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

Hum Mol Genet 2019 Apr 1. Epub 2019 Apr 1.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are two pathologically distinct chronic lung diseases that are associated with cigarette smoking. Genetic studies have identified shared loci for COPD and IPF, including several loci with opposite directions of effect. The existence of additional shared genetic loci, as well as potential shared pathobiological mechanisms between the two diseases at the molecular level, remains to be explored. 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/ddz069DOI Listing
April 2019
2 Reads

Pathogenic effects of agrin V1727F mutation are isoform-specific and decrease its expression and affinity for HSPGs and LRP4.

Hum Mol Genet 2019 Apr 17. Epub 2019 Apr 17.

Department of Physiology and Membrane Biology, University of California Davis, Davis, California, USA.

Agrin is a large extracellular matrix protein whose isoforms differ in their tissue distribution and function. Motoneuron-derived y+z+ agrin regulates the formation of the neuromuscular junction (NMJ), while y-z- agrin is widely expressed and has diverse functions. Previously we identified a missense mutation (V1727F) in the second laminin-G domain (LG2) of agrin that causes severe congenital myasthenic 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/ddz081DOI Listing
April 2019
1 Read

The Landscape of Parkin Variants Reveals Pathogenic Mechanisms and Therapeutic Targets in Parkinson's Disease.

Hum Mol Genet 2019 Apr 17. Epub 2019 Apr 17.

McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Mutations in Parkin (PARK2), which encodes an E3 ubiquitin ligase implicated in mitophagy, are the most common cause of early onset Parkinson's Disease (PD). Hundreds of naturally occurring Parkin variants have been reported, both in PD patient and population databases. However, the effects of the majority of these variants on the function of Parkin and in PD pathogenesis remains unknown. Read More

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http://dx.doi.org/10.1093/hmg/ddz080DOI Listing
April 2019
2 Reads

The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy.

Hum Mol Genet 2019 Mar 5. Epub 2019 Mar 5.

MDUK Oxford Neuromuscular Centre, Department of Physiology, Anatomy and Genetics, Oxford, UK.

Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disorder caused by loss of dystrophin. Several therapeutic modalities are currently in clinical trials but none will achieve maximum functional rescue and full disease correction. Therefore, we explored the potential of combining the benefits of dystrophin with increases of utrophin, an autosomal paralogue of dystrophin. 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/ddz049DOI Listing
March 2019
6 Reads

Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in Nemaline Myopathy.

Hum Mol Genet 2019 Apr 15. Epub 2019 Apr 15.

Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA-02115.

Nemaline myopathy (NM) is the most common form of congenital myopathy that results in hypotonia and muscle weakness. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode for members of the Kelch family of proteins. Kelch proteins act as substrate-specific-adapters for CUL3 E3 ubiquitin ligase to regulate protein turn-over through the ubiquitin-proteasome machinery. 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/ddz078DOI Listing
April 2019
1 Read

The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome.

Hum Mol Genet 2019 Apr 15. Epub 2019 Apr 15.

Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common noncoding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (OR=0. 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/ddz075DOI Listing
April 2019
6 Reads

Rare variants in MYH15 modify amyotrophic lateral sclerosis risk.

Hum Mol Genet 2019 Apr 1. Epub 2019 Apr 1.

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive muscular atrophy and respiratory failure. The G4C2 repeat expansion in the C9orf72 gene is the most prevalent genetic risk for ALS. Mutation carriers (C9ALS) display variability in phenotypes such as age-at-onset and duration, suggesting the existence of additional genetic factors. Read More

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http://dx.doi.org/10.1093/hmg/ddz063DOI Listing

MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration.

Hum Mol Genet 2019 Apr 1. Epub 2019 Apr 1.

Department of Human Genetics.

Disorders of sex development (DSDs) are defined as congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. In many DSD cases, genetic causes remain to be elucidated. Here, we performed a case-control exome sequencing study comparing gene-based burdens of rare damaging variants between 26 DSD cases and 2625 controls. Read More

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http://dx.doi.org/10.1093/hmg/ddz066DOI Listing

Docosahexaenoic acid reduces microglia phagocytic activity via miR-124 and induces neuroprotection in rodent models of spinal cord contusion injury.

Hum Mol Genet 2019 Apr 11. Epub 2019 Apr 11.

Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.

Microglia are activated after spinal cord injury (SCI), but their phagocytic mechanisms and link to neuroprotection remain incompletely characterized. Docosahexaenoic acid (DHA) has been shown to have significant neuroprotective effects after hemisection and compression SCI and can directly affect microglia in these injury models. In rodent contusion SCI, we demonstrate that DHA (500 nmol/kg) administered acutely post-injury confers neuroprotection and enhances locomotor recovery, and also exerts a complex modulation of the microglial response to injury. Read More

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http://dx.doi.org/10.1093/hmg/ddz073DOI Listing

Corrigendum: Perinatal Gjb2 gene transfer rescues hearing in a mouse model of hereditary deafness.

Hum Mol Genet 2019 Feb 28. Epub 2019 Feb 28.

Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1093/hmg/ddz041DOI Listing
February 2019

A longitudinal multimodal in vivo molecular imaging study of the 3xTg-AD mouse model shows progressive early hippocampal and taurine loss.

Hum Mol Genet 2019 Feb 28. Epub 2019 Feb 28.

CNC.IBILI Consortium, University of Coimbra, Portugal.

The understanding of the natural history of Alzheimer's disease (AD) and temporal trajectories of in vivo molecular mechanisms requires longitudinal approaches. A behavioral and multimodal imaging study was performed at 4/8/12 and 16 months of age in a triple transgenic mouse model of AD (3xTg-AD). Behavioral assessment included the open field and novel object recognition tests. Read More

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http://dx.doi.org/10.1093/hmg/ddz045DOI Listing
February 2019
6.393 Impact Factor

BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH).

Hum Mol Genet 2019 Feb 27. Epub 2019 Feb 27.

Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.

Pulmonary Arterial Hypertension (PAH) is a devastating cardiovascular disorder characterised by the remodelling of pre-capillary pulmonary arteries. The vascular remodelling observed in PAH patients results from excessive proliferation and apoptosis resistance of pulmonary arterial smooth muscle (PASMCs) and endothelial cells (PAECs). We have previously demonstrated that mutations in the type II receptor for bone morphogenetic protein (BMPRII) underlie the majority of the familial and inherited forms of the disease. Read More

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http://dx.doi.org/10.1093/hmg/ddz047DOI Listing
February 2019
1 Read

Quantitative proteomics identifies proteins that resist translational repression and become dysregulated in ALS-FUS.

Hum Mol Genet 2019 Feb 26. Epub 2019 Feb 26.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.

Aberrant translational repression is a feature of multiple neurodegenerative diseases. The association between disease-linked proteins and stress granules further implicates impaired stress responses in neurodegeneration. However, our knowledge of the proteins that evade translational repression is incomplete. Read More

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http://dx.doi.org/10.1093/hmg/ddz048DOI Listing
February 2019
1 Read

Sunitinib promotes myogenic regeneration and mitigates disease progression in the mdx mouse model of duchenne muscular dystrophy.

Hum Mol Genet 2019 Feb 26. Epub 2019 Feb 26.

University of Nevada, Reno School of Medicine, Department of Pharmacology, Reno, NV 89557.

Duchenne muscular dystrophy (DMD) is a lethal, muscle degenerative disease causing premature death of affected children. DMD is characterized by mutations in the dystrophin gene that result in a loss of the dystrophin protein. Loss of dystrophin causes an associated reduction in proteins of the dystrophin glycoprotein complex (DGC), leading to contraction-induced sarcolemmal weakening, muscle tearing, fibrotic infiltration and rounds of degeneration and failed regeneration affecting satellite cell populations. Read More

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http://dx.doi.org/10.1093/hmg/ddz044DOI Listing
February 2019
1 Read

Mutational spectrum and clinical signatures in 114 families with hereditary multiple osteochondromas: insights into molecular properties of selected exostosin variants.

Hum Mol Genet 2019 Feb 26. Epub 2019 Feb 26.

Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

Hereditary multiple osteochondromas (HMO) is a rare autosomal dominant skeletal disorder, caused by heterozygous variants in either EXT1 or EXT2, which encode proteins involved in the biogenesis of heparan sulphate. Pathogenesis and genotype-phenotype correlations remain poorly understood. We studied 114 HMO families (158 affected individuals) with causative EXT1 or EXT2 variants identified by Sanger sequencing, or MLPA and qPCR. Read More

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http://dx.doi.org/10.1093/hmg/ddz046DOI Listing
February 2019
3 Reads

Pathological mTOR mutations impact cortical development.

Hum Mol Genet 2019 02 21. Epub 2019 Feb 21.

International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, Warsaw, Poland.

Several mosaic mutations of the mammalian/mechanistic target of rapamycin (mTOR) have recently been found in patients with cortical malformations, such as hemimegalencephaly (HME) and focal cortical dysplasia (FCD). Although all of them should activate mTOR signaling, comparisons of the impact of different mTOR mutations on brain development have been lacking. Also it remains unknown if any potential differences these mutations may have on cortical development are directly related to a degree of mTOR signaling increase. Read More

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http://dx.doi.org/10.1093/hmg/ddz042DOI Listing
February 2019
1 Read

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
12 Reads
6.393 Impact Factor

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
2 Reads

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
2 Reads

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
2 Reads

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
1 Read

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
3 Reads
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
16 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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https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg
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http://dx.doi.org/10.1093/hmg/ddz031DOI Listing
January 2019
6 Reads

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
1 Read

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
10 Reads
6.393 Impact Factor

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
2 Reads

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
5 Reads

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
5 Reads

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
2 Reads
6.393 Impact Factor

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
12 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
18 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
4 Reads

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
3 Reads

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
2 Reads

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
1 Read

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
4 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
3 Reads

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
9 Reads