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Human Molecular Genetics

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https://www.readbyqxmd.com/read/28633508/rescue-of-peripheral-vestibular-function-in-usher-syndrome-mice-using-a-splice-switching-antisense-oligonucleotide
#1
Sarath Vijayakumar, Frederic F Depreux, Francine M Jodelka, Jennifer J Lentz, Frank Rigo, Timothy A Jones, Michelle L Hastings
Usher syndrome type 1C (USH1C/harmonin) is associated with profound retinal, auditory and vestibular dysfunction. We have previously reported on an antisense oligonucleotide (ASO-29) that dramatically improves auditory function and balance behavior in mice homozygous for the harmonin mutation Ush1c c.216G>A following a single systemic administration. The findings were suggestive of improved vestibular function; however, no direct vestibular assessment was made. Here, we measured vestibular sensory evoked potentials (VsEPs) to directly assess vestibular function in Usher mice...
June 19, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28633380/epigallocatechin-3-gallate-and-related-phenol-compounds-redirect-the-amyloidogenic-aggregation-pathway-of-ataxin-3-towards-non-toxic-aggregates-and-prevent-toxicity-in-neural-cells-and-caenorhabditis-elegans-animal-model
#2
Cristina Visentin, Francesca Pellistri, Antonino Natalello, Jacopo Vertemara, Marcella Bonanomi, Elena Gatta, Amanda Penco, Annalisa Relini, Luca De Gioia, Cristina Airoldi, Maria E Regonesi, Paolo Tortora
The protein ataxin-3 (ATX3) triggers an amyloid-related neurodegenerative disease when its polyglutamine stretch is expanded beyond a critical threshold. We formerly demonstrated that the polyphenol epigallocatechin-3-gallate (EGCG) could redirect amyloid aggregation of a full-length, expanded ATX3 (ATX3-Q55) towards non-toxic, soluble, SDS-resistant aggregates. Here, we have characterized other related phenol compounds, although smaller in size, i.e., (-)-epigallocatechin gallate (EGC), and gallic acid (GA)...
June 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28633377/emerging-mechanisms-of-aminoacyl-trna-synthetase-mutations-in-recessive-and-dominant-human-disease
#3
Rebecca Meyer-Schuman, Anthony Antonellis
Aminoacyl-tRNA synthetases (ARSs) are responsible for charging amino acids to cognate tRNA molecules, which is the essential first step of protein translation. Interestingly, mutations in genes encoding ARS enzymes have been implicated in a broad spectrum of human inherited diseases. Bi-allelic mutations in ARSs typically cause severe, early-onset, recessive diseases that affect a wide range of tissues. The vast majority of these mutations show loss-of-function effects and impair protein translation. However, it is not clear how a subset cause tissue-specific phenotypes...
June 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28605435/aav9-delivered-bispecific-nanobody-attenuates-amyloid-burden-in-the-gelsolin-amyloidosis-mouse-model
#4
Adriaan Verhelle, Nisha Nair, Inge Everaert, Wouter Van Overbeke, Lynn Supply, Olivier Zwaenepoel, Cindy Peleman, Jo Van Dorpe, Tony Lahoutte, Nick Devoogdt, Wim Derave, Marinee K Chuah, Thierry VandenDriessche, Jan Gettemans
No abstract text is available yet for this article.
June 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28605434/a-knockin-mouse-model-of-spinocerebellar-ataxia-type-3-exhibits-prominent-aggregate-pathology-and-aberrant-splicing-of-the-disease-gene-transcript
#5
Biswarathan Ramani, Ginny M Harris, Rogerio Huang, Takahiro Seki, Geoffrey G Murphy, Maria do Carmo Costa, Svetlana Fischer, Thomas L Saunders, Guangbin Xia, Richard C McEachin, Henry L Paulson
No abstract text is available yet for this article.
June 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28595361/mitochondrial-dysfunction-underlies-cognitive-defects-as-a-result-of-neural-stem-cell-depletion-and-impaired-neurogenesis
#6
Mireille Khacho, Alysen Clark, Devon S Svoboda, Jason G MacLaurin, Diane C Lagace, David S Park, Ruth S Slack
Mitochondrial dysfunction is a common feature of many genetic disorders that target the brain and cognition. However, the exact role these organelles play in the etiology of such disorders is not understood. Here we show that mitochondrial dysfunction impairs brain development, depletes the adult neural stem cell (NSC) pool and impacts embryonic and adult neurogenesis. Using deletion of the mitochondrial oxidoreductase AIF as a genetic model of mitochondrial and neurodegenerative diseases revealed the importance of mitochondria in multiple steps of the neurogenic process...
June 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28595321/mitochondrial-deficits-and-abnormal-mitochondrial-retrograde-axonal-transport-play-a-role-in-the-pathogenesis-of-mutant-hsp27-induced-charcot-marie-tooth-disease
#7
Bernadett Kalmar, Amy Innes, Klaus Wanisch, Alicia Koyen Kolaszynska, Amelie Pandraud, Gavin Kelly, Andrey Y Abramov, Mary M Reilly, Giampietro Schiavo, Linda Greensmith
Mutations in the small heat shock protein Hsp27, encoded by the HSPB1 gene, have been shown to cause Charcot Marie Tooth Disease type 2 (CMT-2) or distal hereditary motor neuropathy (dHMN). Protein aggregation and axonal transport deficits have been implicated in the disease. In this study, we conducted analysis of bidirectional movements of mitochondria in primary motor neuron axons expressing wild type and mutant Hsp27. We found significantly slower retrograde transport of mitochondria in Ser135Phe, Pro39Leu and Arg140Gly mutant Hsp27 expressing motor neurons than in wild type Hsp27 neurons, although anterograde movement velocities remained normal...
June 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28595297/fgfr2-mutations-in-bent-bone-dysplasia-syndrome-activate-nucleolar-stress-and-perturb-cell-fate-determination
#8
Cynthia L Neben, Creighton T Tuzon, Xiaojing Mao, Fides D Lay, Amy E Merrill
Fibroblast growth factor (FGF) signaling promotes self-renewal in progenitor cells by encouraging proliferation and inhibiting cellular senescence. Yet, these beneficial effects can be hijacked by disease-causing mutations in FGF receptor (FGFR) during embryogenesis. By studying dominant FGFR2 mutations that are germline in Bent Bone Dysplasia Syndrome (BBDS), we reveal a mechanistic connection between FGFR2, ribosome biogenesis, and cellular stress that links cell fate determination to disease pathology. We previously showed that FGFR2 mutations in BBDS, which amplify nucleolar targeting of FGFR2, activate ribosomal DNA (rDNA) transcription and delay differentiation in osteoprogenitor cells and patient-derived bone...
June 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28595270/spp1-genotype-and-glucocorticoid-treatment-modify-osteopontin-expression-in-duchenne-muscular-dystrophy-cells
#9
Sara Vianello, Boris Pantic, Aurora Fusto, Luca Bello, Eva Galletta, Doriana Borgia, Bruno F Gavassini, Claudio Semplicini, Gianni Sorarù, Libero Vitiello, Elena Pegoraro
Glucocorticoids are beneficial in Duchenne muscular dystrophy (DMD). Osteopontin (OPN), the protein product of SPP1, plays a role in DMD pathology modulating muscle inflammation and regeneration. A polymorphism in the SPP1 promoter (rs28357094) has been recognized as a genetic modifier of DMD, and there is evidence suggesting that it modifies response to glucocorticoid treatment. The effect of the glucocorticoid deflazacort on SPP1 mRNA and protein expression was investigated in DMD primary human myoblasts and differentiated myotubes with defined rs28357094 genotype (TT versus TG)...
June 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28595269/identification-of-a-rare-lamb4-variant-associated-with-familial-diverticulitis-through-exome-sequencing
#10
Joel L Coble, Kathryn Sheldon, Feng Yue, Tarik Salameh, Leonard Harris, Sue Deiling, Francesca Ruggiero, Melanie Eshelman, Gregory S Yochum, Walter A Koltun, Glenn S Gerhard, James R Broach
Diverticulitis is a chronic disease of the colon in which diverticuli, or outpouching through the colonic wall, become inflamed. Although recent observations suggests that genetic factors may play a significant role in diverticulitis, few genes have yet been implicated in disease pathogenesis and familial cases are uncommon. Here, we report results of whole exome sequencing performed on members from a single multi-generational family with early onset diverticulitis in order to identify a genetic component of the disease...
June 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28595268/placental-biomarkers-for-assessing-fetal-health
#11
Irina Manokhina, Giulia F Del Gobbo, Chaini Konwar, Samantha L Wilson, Wendy P Robinson
The placenta is a multifunctional organ that regulates key aspects of pregnancy maintenance and fetal development. As the placenta is in direct contact with maternal blood, cellular products (DNA, RNA, proteins, etc.) from the placenta can enter maternal circulation by a variety of ways. The application of serum proteins and circulating placental derived DNA has been well demonstrated for the diagnosis of aneuploidy, and there is great interest in exploring the use of placental biomarkers for the prediction of a range of fetal health parameters...
June 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28582499/dental-pulp-stem-cells-for-the-study-of-neurogenetic-disorders
#12
A Kaitlyn Victor, Lawrence T Reiter
Dental pulp stem cells (DPSC) are a relatively new alternative stem cell source for the study of neurogenetic disorders. DPSC can be obtained non-invasively and collected from long-distances remaining viable during transportation. These highly proliferative cells express stem cell markers and retain the ability to differentiate down multiple cell lineages including chondrocytes, adipocytes, osteoblasts, and multiple neuronal cell types. The neural crest origin of DPSC makes them a useful source of primary cells for modeling neurological disorders at the molecular level...
June 5, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28575497/loss-of-hepatic-lrpprc-alters-mitochondrial-bioenergetics-regulation-of-permeability-transition-and-trans-membrane-ros-diffusion
#13
Alexanne Cuillerier, Shamisa Honarmand, Virgilio J J Cadete, Matthieu Ruiz, Anik Forest, Sonia Deschênes, Claudine Beauchamp, Guy Charron, John D Rioux, Christine Des Rosiers, Eric A Shoubridge, Yan Burelle
BACKGROUND AND AIMS: The French-Canadian variant of Leigh Syndrome (LSFC) is an autosomal recessive oxidative phosphorylation (OXPHOS) disorder caused by a mutation in LRPPRC, coding for a protein involved in the stability of mitochondrially-encoded mRNAs. Low levels of LRPPRC are present in all patient tissues, but result in a disproportionately severe OXPHOS defect in the brain and liver, leading to unpredictable subacute metabolic crises. METHODS: To investigate the impact of the OXPHOS defect in the liver, we analyzed the mitochondrial phenotype in mice harboring an hepatocyte-specific inactivation of Lrpprc...
May 31, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28575328/identification-of-the-amino-acids-inserted-during-suppression-of-cftr-nonsense-mutations-and-determination-of-their-functional-consequences
#14
Xiaojiao Xue, Venkateshwar Mutyam, Amita Thakerar, James Mobley, Robert J Bridges, Steven M Rowe, Kim M Keeling, David M Bedwell
In-frame premature termination codons (PTCs) account for ∼11% of all disease-associated mutations. PTC suppression therapy utilizes small molecules that suppress translation termination at a PTC to restore synthesis of a full-length protein. PTC suppression is mediated by the base pairing of a near-cognate aminoacyl-tRNA with a PTC and subsequently, the amino acid becomes incorporated into the nascent polypeptide at the site of the PTC. However, little is known about the identity of the amino acid(s) inserted at a PTC during this process in mammalian cells, or how the surrounding sequence context influences amino acid incorporation...
May 31, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28575308/spatial-temporal-transcriptional-dynamics-of-long-non-coding-rnas-in-human-brain
#15
Xiao-Qin Zhang, Ze-Lin Wang, Ming-Wai Poon, Jian-Hua Yang
The functional architecture of human brain is greatly determined by the temporal and spatial regulation of the transcription process. However, the spatial and temporal transcriptional landscape of long non-coding RNAs (lncRNAs) during human brain development remains poorly understood. Here, we report the genome-wide lncRNA transcriptional analysis in an extensive series of 1340 post-mortem human brain specimens collected from 16 regions spanning the period from early embryo development to late adulthood. We discovered that lncRNA transcriptome dramatically changed during fetal development, while transited to a surprisingly relatively stable state after birth till the late adulthood...
May 31, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28575206/heterozygote-galactocerebrosidase-galc-mutants-have-reduced-remyelination-and-impaired-myelin-debris-clearance-following-demyelinating-injury
#16
Nicole J Scott-Hewitt, Christopher J Folts, Jessica M Hogestyn, Gavin Piester, Margot Mayer-Pröschel, Mark D Noble
Genome-wide association studies (GWAS) are identifying multiple genetic risk factors for several diseases, but the functional role of these changes remains mostly unknown. Variants in the galactocerebrosidase (GALC) gene, for example, were identified as a risk factor for Multiple Sclerosis (MS); however, potential biological relevance of GALC variants to MS remains elusive. We found that heterozygote GALC mutant mice have reduced myelin debris clearance and diminished remyelination after a demyelinating insult...
May 31, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28575395/novel-mouse-models-of-oculopharyngeal-muscular-dystrophy-opmd-reveal-early-onset-mitochondrial-defects-and-suggest-loss-of-pabpn1-may-contribute-to-pathology
#17
Katherine E Vest, Brittany L Phillips, Ayan Banerjee, Luciano H Apponi, Eric B Dammer, Weiting Xu, Dinghai Zheng, Julia Yu, Bin Tian, Grace K Pavlath, Anita H Corbett
Oculopharyngeal muscular dystrophy (OPMD) is a late onset disease caused by polyalanine expansion in the poly(A) binding protein nuclear 1 (PABPN1). Several mouse models have been generated to study OPMD; however, most of these models have employed transgenic overexpression of alanine-expanded PABPN1. These models do not recapitulate the OPMD patient genotype and PABPN1 overexpression could confound molecular phenotypes. We have developed a knock-in mouse model of OPMD (Pabpn1+/A17) that contains one alanine-expanded Pabpn1 allele under the control of the native promoter and one wild-type Pabpn1 allele...
May 29, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28549178/rhoa-rock-inhibition-improves-the-beneficial-effects-of-glucocorticoid-treatment-in-dystrophic-muscle-implications-for-stem-cell-depletion
#18
Xiaodong Mu, Ying Tang, Koji Takayama, Wanqun Chen, Aiping Lu, Bing Wang, Kurt Weiss, Johnny Huard
Glucocorticoid treatment represents a standard palliative treatment for Duchenne muscular dystrophy (DMD) patients, but various adverse effects have limited this treatment. In an effort to understand the mechanism(s) by which glucocorticoids impart their effects on the dystrophic muscle, and potentially reduce the adverse effects, we have studied the effect of prednisolone treatment in dystrophin/utrophin double knockout (dKO) mice, which exhibit a severe dystrophic phenotype due to rapid muscle stem cell depletion...
May 26, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28549150/primary-congenital-and-developmental-glaucomas
#19
Carly Lewis, Adam Hedberg-Buenz, Adam P DeLuca, Edwin M Stone, Wallace L M Alward, John H Fingert
Glaucoma is the leading cause of irreversible blindness worldwide. Although most glaucoma patients are elderly, congenital glaucoma and glaucomas of childhood are also important causes of visual disability. Primary congenital glaucoma (PCG) is isolated, non-syndromic glaucoma that occurs in the first three years of life and is a major cause of childhood blindness. Other early-onset glaucomas may arise secondary to developmental abnormalities, such as glaucomas that occur with aniridia or as part of Axenfeld-Rieger syndrome...
May 26, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28541509/evidence-that-phosphorylated-ubiquitin-signaling-is-involved-in-the-etiology-of-parkinson-s-disease
#20
Kahori Shiba-Fukushima, Kei-Ichi Ishikawa, Tsuyoshi Inoshita, Nana Izawa, Masashi Takanashi, Shigeto Sato, Osamu Onodera, Wado Akamatsu, Hideyuki Okano, Yuzuru Imai, Nobutaka Hattori
The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (ΔΨm)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy...
May 25, 2017: Human Molecular Genetics
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