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Haploinsufficiency

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https://www.readbyqxmd.com/read/28720899/p32-heterozygosity-protects-against-age-and-diet-induced-obesity-by-increasing-energy-expenditure
#1
Yong Liu, Patrick L Leslie, Aiwen Jin, Koji Itahana, Lee M Graves, Yanping Zhang
Obesity is increasing in prevalence and has become a global public health problem. The main cause of obesity is a perturbation in energy homeostasis, whereby energy intake exceeds energy expenditure. Although mitochondrial dysfunction has been linked to the deregulation of energy homeostasis, the precise mechanism is poorly understood. Here, we identify mitochondrial p32 (also known as C1QBP) as an important regulator of lipid homeostasis that regulates both aerobic and anaerobic energy metabolism. We show that while whole-body deletion of the p32 results in an embryonic lethal phenotype, mice heterozygous for p32 are resistant to age- and high-fat diet-induced ailments, including obesity, hyperglycemia, and hepatosteatosis...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28717667/haploinsufficiency-of-bcl11a-associated-with-cerebellar-abnormalities-in-2p15p16-1-deletion-syndrome
#2
Hiroko Shimbo, Takayuki Yokoi, Noriko Aida, Seiji Mizuno, Hiroshi Suzumura, Junichi Nagai, Kazumi Ida, Yumi Enomoto, Chihiro Hatano, Kenji Kurosawa
BACKGROUND: Chromosome 2p15p16.1 deletion syndrome is a rare genetic disorder characterized by intellectual disability (ID), neurodevelopmental delay, language delay, growth retardation, microcephaly, structural brain abnormalities, and dysmorphic features. More than 30 patients with 2p15p16.1 microdeletion syndrome have been reported in the literature. METHODS: Molecular analysis was performed using microarray-based comparative genomic hybridization (array CGH)...
July 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/28717659/identification-and-characterization-of-variants-and-a-novel-4%C3%A2-bp-deletion-in-the-regulatory-region-of-six6-a-risk-factor-for-primary-open-angle-glaucoma
#3
Mohd Hussain Shah, Noemi Tabanera, Subbaiah Ramasamy Krishnadas, Manju R Pillai, Paola Bovolenta, Periasamy Sundaresan
BACKGROUND: Primary open-angle glaucoma (POAG) is a complex disease of multigenic inheritance and the most common subtype of glaucoma. SIX6 encodes a transcription factor involved in retina, optic nerve, and pituitary development. Previous studies showed a genetic association between the SIX6 locus and POAG, identifying risk alleles. Whether these alleles are present also in the south Indian population is unclear. METHODS: To address this question, the SIX6 gene and an already characterized and highly conserved SIX6 enhancer (Ch14:60974427-60974430) were sequenced in two south Indian cohorts, respectively, composed of 65/65 and 200/200 POAG cases/age-matched controls...
July 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/28712747/selectivity-and-kinetic-requirements-of-hdac-inhibitors-as-progranulin-enhancers-for-treating-frontotemporal-dementia
#4
Angela She, Iren Kurtser, Surya A Reis, Krista Hennig, Jenny Lai, Audrey Lang, Wen-Ning Zhao, Ralph Mazitschek, Bradford C Dickerson, Joachim Herz, Stephen J Haggarty
Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through which GRN is epigenetically regulated remain poorly understood. Using a chemogenomic toolkit, including optoepigenetic probes, we show that inhibition of class I HDACs is sufficient to upregulate PGRN in human neurons, and only inhibitors with apparent fast binding to their target HDAC complexes are capable of enhancing PGRN expression...
July 11, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28710361/the-dental-phenotype-of-hairless-dogs-with-foxi3-haploinsufficiency
#5
Kornelius Kupczik, Alexander Cagan, Silke Brauer, Martin S Fischer
Hairless dog breeds show a form of ectodermal dysplasia characterised by a lack of hair and abnormal tooth morphology. This has been attributed to a semi-dominant 7-base-pair duplication in the first exon of the forkhead box I3 gene (FOXI3) shared by all three breeds. Here, we identified this FOXI3 variant in a historical museum sample of pedigreed hairless dog skulls by using ancient DNA extraction and present the associated dental phenotype. Unlike in the coated wild type dogs, the hairless dogs were characterised in both the mandibular and maxillary dentition by a loss of the permanent canines, premolars and to some extent incisors...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28708858/oscngc13-promotes-seed-setting-rate-by-facilitating-pollen-tube-growth-in-stylar-tissues
#6
Yang Xu, Jie Yang, Yihua Wang, Jiachang Wang, Yang Yu, Yu Long, Yunlong Wang, Huan Zhang, Yulong Ren, Jun Chen, Ying Wang, Xin Zhang, Xiuping Guo, Fuqing Wu, Shanshan Zhu, Qibing Lin, Ling Jiang, Chuanyin Wu, Haiyang Wang, Jianmin Wan
Seed-setting rate is a critical determinant of grain yield in rice (Oryza sativa L.). Rapid and healthy pollen tube growth in the style is required for high seed-setting rate. The molecular mechanisms governing this process remain largely unknown. In this study, we isolate a dominant low seed-setting rate rice mutant, sss1-D. Cellular examination results show that pollen tube growth is blocked in about half of the mutant styles. Molecular cloning and functional assays reveals that SSS1-D encodes OsCNGC13, a member of the cyclic nucleotide-gated channel family...
July 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28702509/loss-of-function-variants-of-scn8a-in-intellectual-disability-without-seizures
#7
Jacy L Wagnon, Bryan S Barker, Matteo Ottolini, Young Park, Alicia Volkheimer, Purnima Valdez, Marielle E M Swinkels, Manoj K Patel, Miriam H Meisler
OBJECTIVE: To determine the functional effect of SCN8A missense mutations in 2 children with intellectual disability and developmental delay but no seizures. METHODS: Genomic DNA was analyzed by next-generation sequencing. SCN8A variants were introduced into the Nav1.6 complementary DNA by site-directed mutagenesis. Channel activity was measured electrophysiologically in transfected ND7/23 cells. The stability of the mutant channels was assessed by Western blot...
August 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28702320/parental-obesity-leads-to-metabolic-changes-in-the-f2-generation-in-drosophila
#8
Rebecca A S Palu, Sophia A Praggastis, Carl S Thummel
OBJECTIVE: A significant portion of the heritable risk for complex metabolic disorders cannot be attributed to classic Mendelian genetic factors. At least some of this missing heritability is thought to be due to the epigenetic influence of parental and grandparental metabolic state on offspring health. Previous work suggests that this transgenerational phenomenon is evolutionarily conserved in Drosophila. These studies, however, have all depended on dietary paradigms to alter parental metabolic state, which can have inconsistent heritable effects on the metabolism of offspring...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28696249/haploinsufficiency-of-the-transcription-factor-ets-1-is-renoprotective-in-dahl-salt-sensitive-rats
#9
Wenguang Feng, Bo Chen, Dongqi Xing, Xingsheng Li, Huma Fatima, Edgar A Jaimes, Paul W Sanders
Studies using Dahl salt-sensitive (SS) rats identified specific quantitative trait loci that predispose animals to hypertension-associated albuminuria and kidney injury. We explored the hypothesis that kidney-specific expression of the transcription factor Ets-1, located within one of these loci on chromosome 8, mediates glomerular injury in SS hypertension. During the first week on a high-salt diet, SS rats and SS rats with only one functioning Ets-1 gene (ES rats) demonstrated similar increases in BP. However, serum creatinine concentration, albuminuria, and glomerular expression of ETS-1 and two ETS-1 targets, MCP-1 and MMP2, did not increase as substantially in ES rats as in SS rats...
July 10, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28696078/the-phenotype-of-ezh2-haploinsufficiency-1-2-mb-deletion-at-7q36-1-in-a-child-with-tall-stature-and-intellectual-disability
#10
Tanay Suri, Abhijit Dixit
Weaver syndrome is a rare overgrowth syndrome with distinct facial features in young children and variable learning disability. Heterozygous missense mutations in EZH2 are present in over 90% of patients with Weaver syndrome but the exact mechanism by which EZH2 mutations cause Weaver syndrome is unknown. We report an 11-year-old boy with a de novo 1.2-Mb deletion at 7q36.1 including EZH2 who has tall stature, significant intellectual disability, and some physical features of Weaver syndrome. Emerging evidence in the literature indicates that Weaver syndrome EZH2 mutations may result in loss of function of the gene and our report suggests that haploinsufficiency of EZH2 may replicate the clinical phenotype of Weaver syndrome...
July 11, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28695822/arid1b-haploinsufficient-mice-reveal-neuropsychiatric-phenotypes-and-reversible-causes-of-growth-impairment
#11
Cemre Celen, Jen-Chieh Chuang, Xin Luo, Nadine Nijem, Angela K Walker, Fei Chen, Shuyuan Zhang, Andrew S Chung, Liem H Nguyen, Ibrahim Nassour, Albert Budhipramono, Xuxu Sun, Levinus A Bok, Meriel McEntagart, Evelien F Gevers, Shari G Birnbaum, Amelia J Eisch, Craig M Powell, Woo-Ping Ge, Gijs We Santen, Maria Chahrour, Hao Zhu
Sequencing studies have implicated haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al...
July 11, 2017: ELife
https://www.readbyqxmd.com/read/28695622/sleep-disturbance-by-pramipexole-is-modified-by-meis1-in-mice
#12
Aaro V Salminen, Barbara Schormair, Cornelia Flachskamm, Miguel Torres, Bertram Müller-Myhsok, Mayumi Kimura, Juliane Winkelmann
Meis homeobox 1 (Meis1) is a transcription factor functioning in the development of the nervous system and the cardiovascular system. Both common and rare variants within the gene have been associated with restless legs syndrome (RLS), while its association with symptoms of insomnia has also been discovered recently. RLS is associated with sleep disturbances, and while Meis1 haploinsufficiency is one of the most promising strategies for an RLS animal model, sleep phenotyping of Meis1 knockout mice has never been conducted...
July 11, 2017: Journal of Sleep Research
https://www.readbyqxmd.com/read/28694332/the-ets2-repressor-factor-erf-is-required-for-effective-primitive-and-definitive-hematopoiesis
#13
Ioanna Peraki, James Palis, George Mavrothalassitis
Erf is a ubiquitously expressed ets-DNA-binding containing transcriptional repressor. Erf haploinsufficiency causes craniosynostosis in human and mice, while its absence in mice leads to failed chorioallantoic fusion and death at E10.5. In this study, we show that Erf is required in all three waves of embryonic hematopoiesis. Mice lacking Erf in embryo proper exhibited severe anemia and died around embryonic day (E) 14.5. Erf epiblast specific knockout embryos had reduced numbers of circulating blood cells from E9...
July 10, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28692064/plk1-regulates-contraction-of-postmitotic-smooth-muscle-cells-and-is-required-for-vascular-homeostasis
#14
Guillermo de Cárcer, Paulina Wachowicz, Sara Martínez-Martínez, Jorge Oller, Nerea Méndez-Barbero, Beatriz Escobar, Alejandra González-Loyola, Tohru Takaki, Aicha El Bakkali, Juan A Cámara, Luis J Jiménez-Borreguero, Xosé R Bustelo, Marta Cañamero, Francisca Mulero, María de Los Ángeles Sevilla, María Jose Montero, Juan Miguel Redondo, Marcos Malumbres
Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo...
July 10, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28692033/spontaneous-loss-of-b-lineage-transcription-factors-leads-to-pre-b-leukemia-in-ebf1-bcl-xl-tg-mice
#15
J A Ramírez-Komo, M A Delaney, D Straign, K Lukin, M Tsang, B M Iritani, J Hagman
Early B-cell factor 1 (EBF1) plays a central role in B-cell lineage specification and commitment. Loss of this critical transcription factor is strongly associated with high-risk, relapsed and therapy-resistant B-cell-acute lymphoblastic leukemia, especially in children. However, Ebf1 haploinsufficient mice exhibit a normal lifespan. To determine whether prolonged survival of B cells would enable tumorigenesis in Ebf1 haploinsufficient animals, we generated Ebf1(+/-)Bcl-xL(Tg) mice, which express the anti-apoptotic factor Bcl-xL in B cells...
July 10, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28691782/a-novel-microduplication-of-arid1b-clinical-genetic-and-proteomic-findings
#16
Catarina M Seabra, Nicholas Szoko, Serkan Erdin, Ashok Ragavendran, Alexei Stortchevoi, Patrícia Maciel, Kathleen Lundberg, Daniela Schlatzer, Janice Smith, Michael E Talkowski, James F Gusella, Marvin R Natowicz
Genetic alterations of ARID1B have been recently recognized as one of the most common mendelian causes of intellectual disability and are associated with both syndromic and non-syndromic phenotypes. The ARID1B protein, a subunit of the chromatin remodeling complex SWI/SNF-A, is involved in the regulation of transcription and multiple downstream cellular processes. We report here the clinical, genetic, and proteomic phenotypes of an individual with a unique apparent de novo mutation of ARID1B due to an intragenic duplication...
July 10, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28690488/a-novel-partial-duplication-of-zeb2-and-review-of-zeb2-involvement-in-mowat-wilson-syndrome
#17
Adrianne L Baxter, Jay L Vivian, R Tanner Hagelstrom, Waheeda Hossain, Wendy L Golden, E Robert Wassman, Rena J Vanzo, Merlin G Butler
Mowat-Wilson syndrome is a rare genetic condition characterized by intellectual disability, structural anomalies, and dysmorphic features. It is caused by haploinsufficiency of the ZEB2 gene in chromosome 2q22.3. Over 180 distinct mutations in ZEB2 have been reported, including nonsense and missense point mutations, deletions, and large chromosomal rearrangements. We report on a 14-year-old female with a clinical diagnosis of Mowat-Wilson syndrome. Chromosomal microarray identified a novel de novo 69-kb duplication containing exons 1 and 2 of the ZEB2 gene...
June 2017: Molecular Syndromology
https://www.readbyqxmd.com/read/28686853/wdr26-haploinsufficiency-causes-a-recognizable-syndrome-of-intellectual-disability-seizures-abnormal-gait-and-distinctive-facial-features
#18
Cara M Skraban, Constance F Wells, Preetha Markose, Megan T Cho, Addie I Nesbitt, P Y Billie Au, Amber Begtrup, John A Bernat, Lynne M Bird, Kajia Cao, Arjan P M de Brouwer, Elizabeth H Denenberg, Ganka Douglas, Kristin M Gibson, Katheryn Grand, Alice Goldenberg, A Micheil Innes, Jane Juusola, Marlies Kempers, Esther Kinning, David M Markie, Martina M Owens, Katelyn Payne, Richard Person, Rolph Pfundt, Amber Stocco, Claire L S Turner, Nienke E Verbeek, Laurence E Walsh, Taylor C Warner, Patricia G Wheeler, Dagmar Wieczorek, Alisha B Wilkens, Evelien Zonneveld-Huijssoon, Tjitske Kleefstra, Stephen P Robertson, Avni Santani, Koen L I van Gassen, Matthew A Deardorff
We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip...
July 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28686619/rare-variants-of-small-effect-size-in-neuronal-excitability-genes-influence-clinical-outcome-in-japanese-cases-of-scn1a-truncation-positive-dravet-syndrome
#19
Michael F Hammer, Atsushi Ishii, Laurel Johnstone, Alexander Tchourbanov, Branden Lau, Ryan Sprissler, Brian Hallmark, Miao Zhang, Jin Zhou, Joseph Watkins, Shinichi Hirose
Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i...
2017: PloS One
https://www.readbyqxmd.com/read/28686577/mtor-raptor-signaling-is-critical-for-skeletogenesis-in-mice-through-the-regulation-of-runx2-expression
#20
Qinggang Dai, Zhan Xu, Xuhui Ma, Ningning Niu, Siru Zhou, Furong Xie, Lingyong Jiang, Jun Wang, Weiguo Zou
The mammalian target of rapamycin (mTOR)/regulatory-associated protein of mTOR (Raptor) pathway transmits and integrates different signals including growth factors, nutrients, and energy metabolism. Nearly all these signals have been found to play roles in skeletal biology. However, the contribution of mTOR/Raptor to osteoblast biology in vivo remains to be elucidated as the conclusions of recent studies are controversial. Here we report that mice with a deficiency of either mTOR or Raptor in preosteoblasts exhibited clavicular hypoplasia and delayed fontanelle fusion, similar to those found in human patients with cleidocranial dysplasia (CCD) haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2) or those identified in Runx2(+/-) mice...
July 7, 2017: Cell Death and Differentiation
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