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Human Molecular Genetics

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https://www.readbyqxmd.com/read/28087737/a-homozygous-mutation-in-trim36-causes-autosomal-recessive-anencephaly-in-an-indian-family
#1
Nivedita Singh, Vishwanath Kumble Bhat, Ankana Tiwari, Srinivas G Kodaganur, Sagar J Tontanahal, Astha Sarda, K V Malini, Arun Kumar
Anencephaly is characterized by the absence of brain tissues and cranium. During primary neurulation stage of the embryo, the rostral part of the neural pore fails to close, leading to anencephaly. Anencephaly shows a heterogeneous etiology, ranging from environmental to genetic causes. The autosomal recessive inheritance of anencephaly has been reported in several populations. In this study, we employed whole-exome sequencing and identified a homozygous missense mutation c.1522C>A (p.Pro508Thr) in the TRIM36 gene as the cause of autosomal recessive anencephaly (APH) in an Indian family...
January 13, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28087736/imputation-of-orofacial-clefting-data-identifies-novel-risk-loci-and-sheds-light-on-the-genetic-background-of-cleft-lip-%C3%A2-cleft-palate-and-cleft-palate-only
#2
Kerstin U Ludwig, Anne C Böhmer, John Bowes, Miloš Nikolić, Nina Ishorst, Niki Wyatt, Nigel L Hammond, Lina Gölz, Frederic Thieme, Sandra Barth, Hannah Schuenke, Johanna Klamt, Malte Spielmann, Khalid Aldhorae, Augusto Rojas-Martinez, Markus M Nöthen, Alvaro Rada-Iglesias, Michael J Dixon, Michael Knapp, Elisabeth Mangold
Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signals within this high-density dataset are enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue...
January 13, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28087735/relationships-linking-emotional-motor-cognitive-and-gabaergic-dysfunctions-in-dystrophin-deficient-mdx-mice
#3
Cyrille Vaillend, Rémi Chaussenot
Alterations in the Duchenne muscular dystrophy (DMD) gene have been associated with enhanced stress reactivity in vertebrate species, suggesting a role for brain dystrophin in fear-related behavioral and cognitive processes. Because the loss of dystrophin (Dp427) reduces clustering of central GABAA receptors, it is suspected that local inhibitory tuning and modulation of neuronal excitability are perturbed in a distributed brain circuit that normally controls such critical behavioral functions. In this study we undertook a large-scale behavioral study to evaluate fear-related behavioral disturbances in dystrophin-deficient mdx mice...
January 13, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28087734/increased-mitophagy-in-the-skeletal-muscle-of-spinal-and-bulbar-muscular-atrophy-patients
#4
Doriana Borgia, Adriana Malena, Marco Spinazzi, Maria Andrea Desbats, Leonardo Salviati, Aaron P Russell, Giovanni Miotto, Laura Tosatto, Elena Pegoraro, Gianni Sorarù, Maria Pennuto, Lodovica Vergani
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by polyglutamine expansion in the androgen receptor (AR) and characterized by the loss of lower motor neurons. Here we investigated pathological processes occurring in muscle biopsy specimens derived from SBMA patients and, as controls, age-matched healthy subjects and patients suffering from amyotrophic lateral sclerosis (ALS) and neurogenic atrophy. We detected atrophic fibers in the muscle of SBMA, ALS and neurogenic atrophy patients...
January 13, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28087733/metformin-restores-the-mitochondrial-network-and-reverses-mitochondrial-dysfunction-in-down-syndrome-cells
#5
Antonella Izzo, Maria Nitti, Nunzia Mollo, Simona Paladino, Claudio Procaccini, Deriggio Faicchia, Gaetano Calì, Rita Genesio, Ferdinando Bonfiglio, Rita Cicatiello, Elena Polishchuk, Roman Polishchuk, Paolo Pinton, Giuseppe Matarese, Anna Conti, Lucio Nitsch
Alterations in mitochondrial activity and morphology have been demonstrated in human cells and tissues from individuals with Down syndrome (DS), as well as in DS mouse models. An impaired activity of the transcriptional coactivator PGC-1α/PPARGC1Adue to the overexpression of chromosome 21 genes, such as NRIP1/RIP140, has emerged as an underlying cause of mitochondrial dysfunction in DS. We tested the hypothesis that the activation of the PGC-1α pathway might indeed reverse this mitochondrial dysfunction.
January 13, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28087732/novel-gnb1-mutations-disrupt-assembly-and-function-of-g-protein-heterotrimers-and-cause-global-developmental-delay-in-humans
#6
Katja Lohmann, Ikuo Masuho, Dipak N Patil, Hauke Baumann, Eva Hebert, Sofia Steinrücke, Daniel Trujillano, Nickolas K Skamangas, Valerija Dobricic, Irina Hüning, Gabriele Gillessen-Kaesbach, Ana Westenberger, Dusanka Savic-Pavicevic, Alexander Münchau, Gabriela Oprea, Christine Klein, Arndt Rolfs, Kirill A Martemyanov
Global developmental delay (GDD), often accompanied by intellectual disability, seizures and other features is a severe, clinically and genetically highly heterogeneous childhood-onset disorder. In cases where genetic causes have been identified, de-novo mutations in neuronally expressed genes are a common scenario. These mutations can be best identified by exome sequencing of parent-offspring trios. De novo mutations in the guanine nucleotide-binding protein, beta 1 (GNB1) gene, encoding the Gβ1 subunit of heterotrimeric G proteins, have recently been identified as a novel genetic cause of GDD...
January 13, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28087731/increased-nbcn1-expression-na-hco3-co-transport-and-intracellular-ph-in-human-vascular-smooth-muscle-cells-with-a-risk-allele-for-hypertension
#7
Fu Liang Ng, Ebbe Boedtkjer, Katarzyna Witkowska, Meixia Ren, Ruoxin Zhang, Arthur Tucker, Christian Aalkjær, Mark J Caulfield, Shu Ye
Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na(+)/HCO3 co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. In both cell types, we found genotype-dependent differences for rs13082711 in DNA-nuclear protein interactions, where the risk allele is associated with increased SLC4A7 expression level, NBCn1 availability and function as reflected in elevated steady-state pHi and accelerated recovery from intracellular acidosis...
January 13, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28082376/axonal-ribosomes-and-mrnas-associate-with-fragile-x-granules-in-adult-rodent-and-human-brains
#8
Michael R Akins, Hanna E Berk-Rauch, Kenneth Y Kwan, Molly E Mitchell, Katherine A Shepard, Lulu I T Korsak, Emily E Stackpole, Jennifer L Warner-Schmidt, Nenad Sestan, Heather A Cameron, Justin R Fallon
Local mRNA translation in growing axons allows for rapid and precise regulation of protein expression in response to extrinsic stimuli. However, the role of local translation in mature CNS axons is unknown. Such a mechanism requires the presence of translational machinery and associated mRNAs in circuit-integrated brain axons. Here we use a combination of genetic, quantitative imaging and super-resolution microscopy approaches to show that mature axons in the mammalian brain contain ribosomes, the translational regulator FMRP and a subset of FMRP mRNA targets...
January 12, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28073928/evidence-of-epigenetic-admixture-in-the-colombian-population
#9
Konrad Rawlik, Amy Rowlatt, María Carolina Sanabria-Salas, Gustavo Hernández-Suárez, Martha Lucía Serrano López, Jovanny Zabaleta, Albert Tenesa
DNA methylation (DNAm) measured in lymphoblastoid cell lines has been repeatedly demonstrated to differ between various human populations. Due to the role that DNAm plays in controlling gene expression, these differences could significantly contribute to ethnic phenotypic differences. However, because previous studies have compared distinct ethnic groups where genetic and environmental context are confounded, their relative contribution to phenotypic differences between ethnicities remains unclear. Using DNAm assayed in whole blood and colorectal tissue of 132 admixed individuals from Colombia, we identified sites where differential DNAm levels were associated with the local ancestral genetic context...
January 10, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28073927/new-insights-into-the-genetics-of-primary-open-angle-glaucoma-based-on-meta-analyses-of-intraocular-pressure-and-optic-disc-characteristics
#10
Henriët Springelkamp, Adriana I Iglesias, Aniket Mishra, René Höhn, Robert Wojciechowski, Anthony P Khawaja, Abhishek Nag, Ya Xing Wang, Jie Jin Wang, Gabriel Cuellar-Partida, Jane Gibson, Jessica N Cooke Bailey, Eranga N Vithana, Puya Gharahkhani, Thibaud Boutin, Wishal D Ramdas, Tanja Zeller, Robert N Luben, Ekaterina Yonova-Doing, Ananth C Viswanathan, Seyhan Yazar, Angela J Cree, Jonathan L Haines, Jia Yu Koh, Emmanuelle Souzeau, James F Wilson, Najaf Amin, Christian Müller, Cristina Venturini, Lisa S Kearns, Jae Hee Kang, Neighborhood Consortium, Yih Chung Tham, Tiger Zhou, Elisabeth M van Leeuwen, Stefan Nickels, Paul Sanfilippo, Jiemin Liao, Herma van der Linde, Wanting Zhao, Leonieke M E van Koolwijk, Li Zheng, Fernando Rivadeneira, Mani Baskaran, Sven J van der Lee, Shamira Perera, Paulus T V M de Jong, Ben A Oostra, André G Uitterlinden, Qiao Fan, Albert Hofman, E- Shyong Tai, Johannes R Vingerling, Xueling Sim, Roger C W Wolfs, Yik Ying Teo, Hans G Lemij, Chiea Chuen Khor, Rob Willemsen, Karl J Lackner, Tin Aung, Nomdo M Jansonius, Grant Montgomery, Philipp S Wild, Terri L Young, Kathryn P Burdon, Pirro G Hysi, Louis R Pasquale, Tien Yin Wong, Caroline C W Klaver, Alex W Hewitt, Jost B Jonas, Paul Mitchell, Andrew J Lotery, Paul J Foster, Veronique Vitart, Norbert Pfeiffer, Jamie E Craig, David A Mackey, Christopher J Hammond, Janey L Wiggs, Ching-Yu Cheng, Cornelia M van Duijn, Stuart MacGregor
Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup disc ratio (VCDR) and 1 new region associated with IOP...
January 10, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28073926/mutations-of-pqbp1-in-renpenning-syndrome-promote-ubiquitin-mediated-degradation-of-fmrp-and-cause-synaptic-dysfunction
#11
Xiao-Yan Zhang, Junxia Qi, Yu-Qian Shen, Xian Liu, An Liu, Zikai Zhou, Junhai Han, Zi Chao Zhang
Renpenning syndrome is a group of X-linked intellectual disability (XLID) syndromes caused by mutations in human polyglutamine-binding protein 1 (PQBP1) gene. Little is known about the molecular pathogenesis of the various mutations that cause the notable variability in patients. In this study, we examine the cellular and synaptic functions of the most common mutations found in the patients: c.461_462delAG, c.459_462delAGAG, and c.463_464dupAG in an AG hexamer in PQBP1 exon 4. We discovered that PQBP1 c.459_462delAGAG and c...
January 10, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28073925/progranulin-regulates-lysosomal-function-and-biogenesis-through-acidification-of-lysosomes
#12
Yoshinori Tanaka, Genjiro Suzuki, Takashi Matsuwaki, Masato Hosokawa, Geidy Serrano, Thomas G Beach, Keitaro Yamanouchi, Masato Hasegawa, Masugi Nishihara
Progranulin (PGRN) haploinsufficiency resulting from loss-of-function mutations in the PGRN gene causes frontotemporal lobar degeneration accompanied by TDP-43 accumulation, and patients with homozygous mutations in the PGRN gene present with neuronal ceroid lipofuscinosis. Although it remains unknown why PGRN deficiency causes neurodegenerative diseases, there is increasing evidence that PGRN is implicated in lysosomal functions. Here, we show PGRN is a secretory lysosomal protein that regulates lysosomal function and biogenesis by controlling the acidification of lysosomes...
January 10, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28069797/oligodendrocyte-development-and-cns-myelination-are-unaffected-in-a-mouse-model-of-severe-spinal-muscular-atrophy
#13
Ryan W O'Meara, Sarah E Cummings, Yves De Repentigny, Emily McFall, John-Paul Michalski, Marc-Olivier Deguise, Sabrina Gibeault, Rashmi Kothary
The childhood neurodegenerative disease spinal muscular atrophy (SMA) is caused by loss-of-function mutations or deletions in the Survival Motor Neuron 1 (SMN1) gene resulting in insufficient levels of survival motor neuron (SMN) protein. Classically considered a motor neuron disease, increasing evidence now supports SMA as a multi-system disorder with phenotypes discovered in cortical neuron, astrocyte, and Schwann cell function within the nervous system. In this study, we sought to determine whether Smn was critical for oligodendrocyte (OL) development and central nervous system myelination...
January 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28069796/high-dietary-folate-in-pregnant-mice-leads-to-pseudo-mthfr-deficiency-and-altered-methyl-metabolism-with-embryonic-growth-delay-and-short-term-memory-impairment-in-offspring
#14
Renata H Bahous, Nafisa M Jadavji, Liyuan Deng, Marta Cosín-Tomás, Jessica Lu, Olga Malysheva, Kit-Yi Leung, Ming-Kai Ho, Mercè Pallàs, Perla Kaliman, Nicholas DE Greene, Barry J Bedell, Marie A Caudill, Rima Rozen
Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C>T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring...
January 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28069795/intraflagellar-transport-88-ift88-is-crucial-for-craniofacial-development-in-mice-and-is-a-candidate-gene-for-human-cleft-lip-and-palate
#15
Hua Tian, Jifan Feng, Jingyuan Li, Thach-Vu Ho, Yuan Yuan, Yang Liu, Frederick Brindopke, Jane C Figueiredo, William Magee, Pedro A Sanchez-Lara, Yang Chai
Ciliopathies are pleiotropic human diseases resulting from defects of the primary cilium, and these patients often have cleft lip and palate. IFT88 is required for the assembly and function of the primary cilia, which mediate the activity of key developmental signaling pathways. Through whole exome sequencing of a family of three affected siblings with isolated cleft lip and palate, we discovered that they share a novel missense mutation in IFT88 (c.915G>C, p.E305D), suggesting this gene should be considered a candidate for isolated orofacial clefting...
January 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28069794/brain-ventriculomegaly-in-down-syndrome-mice-is-caused-by-pcp4-dose-dependent-cilia-dysfunction
#16
Matthieu Raveau, Takashi Nakahari, Sachie Asada, Keiichi Ishihara, Kenji Amano, Atsushi Shimohata, Haruhiko Sago, Kazuhiro Yamakawa
Down syndrome is a leading cause of congenital intellectual disability caused by an additional copy of the chromosome 21. Patients display physiological and morphological changes affecting the brain and its function. Previously we showed that Ts1Cje and Ts2Cje, Down syndrome mouse models carrying overlapping trisomic segments of different length, show similar ventriculomegaly and neurogenesis dysfunction leading to the hypothesis of a cause-consequence relationship between these phenotypes. However, we here discovered that Ts1Rhr Down syndrome model, carrying an even shorter trisomic segment, was sufficient to trigger ventricular enlargement and ependymal cilia beating deficiency without affecting neurogenesis...
January 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28069793/decreased-wnt-%C3%AE-catenin-signalling-contributes-to-the-pathogenesis-of-dilated-cardiomyopathy-caused-by-mutations-in-the-lamin-a-c-gene
#17
Caroline Le Dour, Coline Macquart, Fusako Sera, Shunichi Homma, Gisele Bonne, John P Morrow, Howard J Worman, Antoine Muchir
Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is characterized by cardiac conduction abnormalities and left ventricular systolic dysfunction predisposing to heart failure. Previous cardiac transcriptional profiling of Lmna(H222P/H222P) mouse, a small animal model of LMNA cardiomyopathy, suggested decreased WNT/β-catenin signalling. We confirmed decreased WNT/β-catenin signalling in the hearts of these mice by demonstrating decreased β-catenin and WNT proteins...
January 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28069792/targeting-ent1-and-adenosine-tone-for-the-treatment-of-huntington-s-disease
#18
Yu-Han Kao, Meng-Syuan Lin, Chiung-Mei Chen, Yih-Ru Wu, Hui-Mei Chen, Hsing-Lin Lai, Yijuang Chern, Chun-Jung Lin
Huntington's disease (HD) is caused by an abnormal CAG expansion in the exon 1 of huntingtin gene. The treatment of HD is an unmet medical need. Given the important role of adenosine in modulating brain activity, in this study, levels of adenosine and adenine nucleotides in the cerebral spinal fluid of patients with HD and in the brain of two mouse models of HD (R6/2 and Hdh(150Q)) were analysed. The expression and activity of ENT1 in the striatum of mice with HD were measured. Targeting adenosine tone for treating HD was examined in R6/2 mice by genetic removal of ENT1 and by giving an ENT1 inhibitor, respectively...
January 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28065882/rescue-of-mutant-rhodopsin-traffic-by-metformin-induced-ampk-activation-accelerates-photoreceptor-degeneration
#19
Dimitra Athanasiou, Monica Aguila, Chikwado A Opefi, Kieron South, James Bellingham, Dalila Bevilacqua, Peter M Munro, Naheed Kanuga, Francesca E Mackenzie, Adam M Dubis, Anastasios Georgiadis, Anna B Graca, Rachael A Pearson, Robin R Ali, Sanae Sakami, Krzysztof Palczewski, Michael Y Sherman, Philip J Reeves, Michael E Cheetham
Protein misfolding caused by inherited mutations leads to loss of protein function and potentially toxic 'gain of function', such as the dominant P23H rhodopsin mutation that causes retinitis pigmentosa (RP). Here, we tested whether the AMPK activator metformin could affect the P23H rhodopsin synthesis and folding. In cell models, metformin treatment improved P23H rhodopsin folding and traffic. In animal models of P23H RP, metformin treatment successfully enhanced P23H traffic to the rod outer segment, but this led to reduced photoreceptor function and increased photoreceptor cell death...
January 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28062667/smn-deficiency-negatively-impacts-red-pulp-macrophages-and-spleen-development-in-mouse-models-of-spinal-muscular-atrophy
#20
Marie-Therese Khairallah, Jacob Astroski, Sarah K Custer, Elliot J Androphy, Craig L Franklin, Christian L Lorson
Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease that is the leading genetic cause of infantile death. It is caused by severe deficiency of the ubiquitously expressed Survival Motor Neuron (SMN) protein. SMA is characterized by α-lower motor neuron loss and muscle atrophy, however, there is a growing list of tissues impacted by SMN deficiency beyond motor neurons. The non-neuronal defects are observed in the most severe Type I SMA patients and most of the widely used SMA mouse models, however, as effective therapeutics are developed, it is unclear whether additional symptoms will be uncovered in longer lived patients...
January 5, 2017: Human Molecular Genetics
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