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Haploinsufficiency

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https://www.readbyqxmd.com/read/29152155/chibby-1-a-new-component-of-%C3%AE-catenin-signaling-in-chronic-myeloid-leukemia
#1
REVIEW
Manuela Mancini, Simona Soverini, Gabriele Gugliotta, Maria Alessandra Santucci, Gianantonio Rosti, Michele Cavo, Giovanni Martinelli, Fausto Castagnetti
Chibby 1 (CBY1) is a small and evolutionarily conserved protein, which act as β-catenin antagonist. CBY1 is encoded by C22orf2 (22q13.1) Its antagonistic function on β-catenin involves the direct interaction with: The C-terminal activation domain of β-catenin, which hinders β-catenin binding with Tcf/Lef transcription factors hence repressing β-catenin transcriptional activation. 14-3-3 scaffolding proteins (σ or ξ), which drive CBY1 nuclear export into a stable tripartite complex with β-catenin. The relative proximity of C22orf2 gene encoding for CBY1 to the BCR breakpoint on chromosome 22q11, whose translocation and rearrangement with the c-ABL is the causative event of chronic myeloid leukemia (CML), suggested that gene haploinsufficiency may play a role in the disease pathogenesis and progression...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29145451/stromal-interaction-molecule-1-haploinsufficiency-causes-maladaptive-response-to-pressure-overload
#2
Takayoshi Ohba, Hiroyuki Watanabe, Manabu Murakami, Kenji Iino, Takeshi Adachi, Yoshihiro Baba, Tomohiro Kurosaki, Kyoichi Ono, Hiroshi Ito
Stromal interaction molecule 1 (STIM1), an endo/sarcoplasmic reticulum Ca2+ sensor, has been shown to control a Ca2+-dependent signal that promotes cardiac hypertrophy. However, whether STIM1 has adaptive role that helps to protect against cardiac overload stress remains unknown. We hypothesized that STIM1 deficiency causes a maladaptive response to pressure overload stress. We investigated STIM1 heterozygous KO (STIM1+/-) mice hearts, in which STIM1 protein levels decreased to 27% of wild-type (WT) with no compensatory increase in STIM2...
2017: PloS One
https://www.readbyqxmd.com/read/29143824/pd-1-is-a-haploinsufficient-suppressor-of-t-cell-lymphomagenesis
#3
Tim Wartewig, Zsuzsanna Kurgyis, Selina Keppler, Konstanze Pechloff, Erik Hameister, Rupert Öllinger, Roman Maresch, Thorsten Buch, Katja Steiger, Christof Winter, Roland Rad, Jürgen Ruland
T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events...
November 15, 2017: Nature
https://www.readbyqxmd.com/read/29142763/array-characterization-of-prenatally-diagnosed-15q26-microdeletion-and-2q37-1-duplication-report-of-a-new-case-with-multicystic-kidneys-and-review-of-the-literature
#4
Molka Kammoun, Wafa Slimani, Hanene Hannachi, Mohamed Bibi, Ali Saad, Soumaya Mougou-Zerelli
We report on a molecular cytogenetic characterization of 15q26 deletion and 2q37.1 duplication in a fetus presenting with intrauterine growth restriction (IUGR), diaphragmatic hernia, multicystic kidneys, left kidney pyelectasis, and clubfeet. A terminal 15q26 deletion and a terminal 2q duplication of at least 10 and 9 Mb, respectively, derived from a maternal translocation, were found. The 15q26 deletion represents a contiguous gene deletion syndrome mainly characterized by IUGR, congenital diaphragmatic hernia, and less frequently kidney defects...
December 2017: Journal of Pediatric Genetics
https://www.readbyqxmd.com/read/29142006/characterization-of-neuroendocrine-tumors-in-heterozygous-mutant-menx-rats-a-novel-model-of-invasive-medullary-thyroid-carcinoma
#5
Sara Molatore, Andrea Kügler, Martin Irmler, Tobias Wiedemann, Frauke Neff, Annette Feuchtinger, Johannes Beckers, Mercedes Robledo, Frederico Roncaroli, Natalia S Pellegata
Rats affected by the MENX syndrome spontaneously develop multiple neuroendocrine tumors (NETs) including adrenal, pituitary and thyroid gland neoplasms. MENX was initially reported to be inherited as a recessive trait and affected rats were found to be homozygous for the predisposing Cdkn1b mutation encoding p27. We here report that heterozygous MENX mutant rats (p27+/mut) develop the same spectrum of NETs seen in the homozygous (p27mut/mut) animals but with slower progression. Consequently, p27+/mut rats have a significantly shorter lifespan compared with their wild-type (p27+/+) littermates...
November 15, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29136300/comments-to-compound-heterozygotes-for-filaggrin-gene-mutations-do-not-always-show-severe-atopic-dermatitis
#6
Luigi Auricchio
recent paper by Akiyama and coworkers questions one more time about role of FLG in A.D.Since first reports of heterozygous mutations of FLG in A.D. patients (1) replicated in northern European populations (2-3-4) and therefore in other populations worldwide (5), genetic studies of patient with I.V. /intrinsic A.D. of different populations of different ancestry as African American (6), and Ethiopian (7) make clear that haploinsufficiency of other structural proteins of epidermis are pathogenic for this phenotype and confirmed the Elias et al...
November 14, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/29133852/nitrosynapsin-therapy-for-a-mouse-mef2c-haploinsufficiency-model-of-human-autism
#7
Shichun Tu, Mohd Waseem Akhtar, Rosa Maria Escorihuela, Alejandro Amador-Arjona, Vivek Swarup, James Parker, Jeffrey D Zaremba, Timothy Holland, Neha Bansal, Daniel R Holohan, Kevin Lopez, Scott D Ryan, Shing Fai Chan, Li Yan, Xiaofei Zhang, Xiayu Huang, Abdullah Sultan, Scott R McKercher, Rajesh Ambasudhan, Huaxi Xu, Yuqiang Wang, Daniel H Geschwind, Amanda J Roberts, Alexey V Terskikh, Robert A Rissman, Eliezer Masliah, Stuart A Lipton, Nobuki Nakanishi
Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c (+/-)(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death...
November 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/29130932/p120-catenin-is-an-obligate-haploinsufficient-tumor-suppressor-in-intestinal-neoplasia
#8
Sarah P Short, Jumpei Kondo, Whitney G Smalley-Freed, Haruna Takeda, Michael R Dohn, Anne E Powell, Robert H Carnahan, Mary K Washington, Manish Tripathi, D Michael Payne, Nancy A Jenkins, Neal G Copeland, Robert J Coffey, Albert B Reynolds
p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an "obligatory" haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated with a significant increase in tumor multiplicity, loss of both alleles was never observed in tumors from these mice. Moreover, forced ablation of the second allele did not further enhance tumorigenesis, but instead induced synthetic lethality in combination with Apc loss of heterozygosity...
November 13, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29130599/interstitial-microdeletion-of-17q11-2-is-associated-with-hypotonia-fatigue-intellectual-disability-and-a-subtle-facial-phenotype-in-three-unrelated-patients
#9
Deborah Osio, Julia Rankin, Hannele Koillinen, Adele Reynolds, Hilde Van Esch
Over the past decade chromosomal microarray analysis (array CGH) has allowed the discovery of many novel disease-causing recurrent microdeletion and microduplication syndromes. Here we present three unrelated patients (2F; 1M) from three different countries, with developmental delay, intellectual disability, hypotonia, fatigue, and highly similar dysmorphic facial features. Shared facial features are a broad and wide forehead, similar shape of the eyes with long palpebral fissures, a bulbous tip of the nose and thick lips...
November 12, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29129316/functional-consequences-of-chrna7-copy-number-alterations-in-induced-pluripotent-stem-cells-and-neural-progenitor-cells
#10
Madelyn A Gillentine, Jiani Yin, Aleksandar Bajic, Ping Zhang, Steven Cummock, Jean J Kim, Christian P Schaaf
Copy-number variants (CNVs) of chromosome 15q13.3 manifest clinically as neuropsychiatric disorders with variable expressivity. CHRNA7, encoding for the α7 nicotinic acetylcholine receptor (nAChR), has been suggested as a candidate gene for the phenotypes observed. Here, we used induced pluripotent stem cells (iPSCs) and neural progenitor cells (NPCs) derived from individuals with heterozygous 15q13.3 deletions and heterozygous 15q13.3 duplications to investigate the CHRNA7-dependent molecular consequences of the respective CNVs...
November 4, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29128567/haploinsufficiency-of-hnrnp-u-changes-activity-pattern-and-metabolic-rhythms
#11
Beibei Lai, Jianghuan Zou, Zhaoyu Lin, Zhipeng Qu, Anying Song, Ying Xu, Xiang Gao
The neuropeptides arginine vasopressin (Avp) and vasoactive intestinal polypeptide (Vip) are critical for the communication and coupling of suprachiasmatic nucleus neurons, which organize daily rhythms of physiology and behavior in mammals. However, how these peptides are regulated remains uncharacterized. We found that heterogeneous nuclear ribonucleoprotein U (hnRNP U) is essential for the expression of Avp and Vip. Loss of one copy of the Hnrnpu gene resulted in fragmented locomotor activities and disrupted metabolic rhythms...
November 9, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/29114001/impaired-central-pulsatile-hemodynamics-in-children-and-adolescents-with-marfan-syndrome
#12
Andrea Grillo, Paolo Salvi, Susan Marelli, Lan Gao, Lucia Salvi, Andrea Faini, Giuliana Trifirò, Renzo Carretta, Alessandro Pini, Gianfranco Parati
BACKGROUND: Marfan syndrome is characterized by aortic root dilation, beginning in childhood. Data about aortic pulsatile hemodynamics and stiffness in pediatric age are currently lacking. METHODS AND RESULTS: In 51 young patients with Marfan syndrome (12.0±3.3 years), carotid tonometry was performed for the measurement of central pulse pressure, pulse pressure amplification, and aortic stiffness (carotid-femoral pulse wave velocity). Patients underwent an echocardiogram at baseline and at 1 year follow-up and a genetic evaluation...
November 7, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29111856/vascular-derived-connective-tissue-growth-factor-ctgf-is-critical-for-pregnancy-induced-%C3%AE-cell-hyperplasia-in-adult-mice
#13
Raymond C Pasek, Jennifer C Dunn, Joseph M Elsakr, Mounika Aramandla, Anveetha R Matta, Maureen Gannon
During pregnancy, maternal β cells undergo compensatory changes including hypertrophy, hyperplasia, and increased glucose-stimulated insulin secretion (GSIS). Failure of these adaptations to occur can result in gestational diabetes mellitus. The secreted protein, Connective tissue growth factor (Ctgf), is critical for normal β cell development and promotes regeneration after partial β cell ablation. During embryogenesis, Ctgf is expressed in pancreatic ducts, vasculature, and β cells. In the adult pancreas, Ctgf is expressed only in the vasculature...
November 7, 2017: Islets
https://www.readbyqxmd.com/read/29111013/genotype-phenotype-and-oct-correlations-in-autosomal-dominant-optic-atrophy-related-to-opa1-gene-mutations-report-of-13-italian-families
#14
E Pretegiani, F Rosini, A Rufa, G N Gallus, E Cardaioli, P Da Pozzo, S Bianchi, V Serchi, M Collura, R Franceschini, S Bianchi Marzoli, M T Dotti, A Federico
Mutations in OPA1 are responsible of 32-89% cases of Autosomal Dominant Optic Atrophy (ADOA). OPA1 ADOA usually presents in childhood with bilateral, progressive visual loss due to retinal ganglion cells neurodegeneration, but environmental factors are supposed to influence onset and phenotype. Sixty Italian OPA1 mutations carriers (fifty-two symptomatic), belonging to thirteen families, underwent neuro-ophthalmologic evaluation. Visual acuity (n=60) and Optical Coherence Tomography (OCT) (n=12) were compared in missense mutations (OPA-M) versus haploinsufficiency-inducing mutations (OPA-H) and correlated with age...
November 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/29107646/spastic-paraplegia-type-31-a-novel-reep1-splice-site-donor-variant-and-expansion-of-the-phenotype-variability
#15
Masaki Kamada, Toshitaka Kawarai, Ryosuke Miyamoto, Rie Kawakita, Yuki Tojima, Celeste Montecchiani, Laura D'Onofrio, Carlo Caltagirone, Antonio Orlacchio, Ryuji Kaji
Mutations in REEP1 have been identified in three types of neurological disorders, autosomal dominant form of Hereditary Spastic Paraplegia type 31 (SPG31), autosomal dominant distal hereditary motor neuronopathy type VB (HMN5B), and autosomal recessive form of congenital axonal neuropathy and diaphragmatic palsy. Previous studies demonstrated different molecular pathogenesis in SPG31, including loss-of-function, gain-of-function and haploinsufficiency. A four-generation family from Japan, including 12 members, was investigated clinically and genetically...
October 21, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29104234/dupuytren-s-and-ledderhose-diseases-in-a-family-with-lmna-related-cardiomyopathy-and-a-novel-variant-in-the-aste1-gene
#16
Michael V Zaragoza, Cecilia H H Nguyen, Halida P Widyastuti, Linda A McCarthy, Anna Grosberg
Dupuytren's disease (palmar fibromatosis) involves nodules in fascia of the hand that leads to flexion contractures. Ledderhose disease (plantar fibromatosis) is similar with nodules of the foot. While clinical aspects are well-described, genetic mechanisms are unknown. We report a family with cardiac disease due to a heterozygous LMNA mutation (c.736C>T, p.Gln246Stop) with palmar/plantar fibromatosis and investigate the hypothesis that a second rare DNA variant increases the risk for fibrotic disease in LMNA mutation carriers...
November 1, 2017: Cells
https://www.readbyqxmd.com/read/29100920/4q25-microdeletion-encompassing-pitx2-a-patient-presenting-with-tetralogy-of-fallot-and-dental-anomalies-without-ocular-features
#17
P Vande Perre, C Zazo Seco, O Patat, L Bouneau, A Vigouroux, D Bourgeois, S El Hout, N Chassaing, P Calvas
Axenfeld-Rieger syndrome (ARS) is a heterogeneous clinical entity transmitted in an autosomal dominant manner. The main feature, Axenfeld-Rieger Anomaly (ARA), is a malformation of the anterior segment of the eye that can lead to glaucoma and impair vision. Extra-ocular defects have also been reported. Point mutations of FOXC1 and PITX2 are responsible for about 40% of the ARS cases. We describe the phenotype of a patient carrying a deletion encompassing the 4q25 locus containing PITX2 gene. This child presented with a congenital heart defect (Tetralogy of Fallot, TOF) and no signs of ARA...
October 31, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29098173/the-roles-of-endoglin-gene-in-cerebrovascular-diseases
#18
Wan Zhu, Li Ma, Rui Zhang, Hua Su
Endoglin (ENG, also known as CD105) is a transforming growth factor β (TGFβ) associated receptor and is required for both vasculogenesis and angiogenesis. Angiogenesis is important in the development of cerebral vasculature and in the pathogenesis of cerebral vascular diseases. ENG is an essential component of the endothelial nitric oxide synthase activation complex. Animal studies showed that ENG deficiency impairs stroke recovery. ENG deficiency also impairs the regulation of vascular tone, which contributes to the pathogenesis of brain arteriovenous malformation (bAVM) and vasospasm...
2017: Neuroimmunology and Neuroinflammation
https://www.readbyqxmd.com/read/29097519/ribosomopathies-there-s-strength-in-numbers
#19
REVIEW
Eric W Mills, Rachel Green
Ribosomopathies are a group of human disorders most commonly caused by ribosomal protein haploinsufficiency or defects in ribosome biogenesis. These conditions manifest themselves as physiological defects in specific cell and tissue types. We review current molecular models to explain ribosomopathies and attempt to reconcile the tissue specificity of these disorders with the ubiquitous requirement for ribosomes in all cells. Ribosomopathies as a group are diverse in their origins and clinical manifestations; we use the well-described Diamond-Blackfan anemia (DBA) as a specific example to highlight some common features...
November 3, 2017: Science
https://www.readbyqxmd.com/read/29093661/syndromic-craniosynostosis-can-define-new-candidate-genes-for-suture-development-or-result-from-the-non-specifc-effects-of-pleiotropic-genes-rasopathies-and-chromatinopathies-as-examples
#20
REVIEW
Marcella Zollino, Serena Lattante, Daniela Orteschi, Silvia Frangella, Paolo N Doronzio, Ilaria Contaldo, Eugenio Mercuri, Giuseppe Marangi
Craniosynostosis is a heterogeneous condition caused by the premature fusion of cranial sutures, occurring mostly as an isolated anomaly. Pathogenesis of non-syndromic forms of craniosynostosis is largely unknown. In about 15-30% of cases craniosynostosis occurs in association with other physical anomalies and it is referred to as syndromic craniosynostosis. Syndromic forms of craniosynostosis arise from mutations in genes belonging to the Fibroblast Growth Factor Receptor (FGFR) family and the interconnected molecular pathways in most cases...
2017: Frontiers in Neuroscience
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