Publications by authors named "Megha Desai"

10 Publications

  • Page 1 of 1

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.

Authors:
Francesca Clementina Radio Kaifang Pang Andrea Ciolfi Michael A Levy Andrés Hernández-García Lucia Pedace Francesca Pantaleoni Zhandong Liu Elke de Boer Adam Jackson Alessandro Bruselles Haley McConkey Emilia Stellacci Stefania Lo Cicero Marialetizia Motta Rosalba Carrozzo Maria Lisa Dentici Kirsty McWalter Megha Desai Kristin G Monaghan Aida Telegrafi Christophe Philippe Antonio Vitobello Margaret Au Katheryn Grand Pedro A Sanchez-Lara Joanne Baez Kristin Lindstrom Peggy Kulch Jessica Sebastian Suneeta Madan-Khetarpal Chelsea Roadhouse Jennifer J MacKenzie Berrin Monteleone Carol J Saunders July K Jean Cuevas Laura Cross Dihong Zhou Taila Hartley Sarah L Sawyer Fabíola Paoli Monteiro Tania Vertemati Secches Fernando Kok Laura E Schultz-Rogers Erica L Macke Eva Morava Eric W Klee Jennifer Kemppainen Maria Iascone Angelo Selicorni Romano Tenconi David J Amor Lynn Pais Lyndon Gallacher Peter D Turnpenny Karen Stals Sian Ellard Sara Cabet Gaetan Lesca Joset Pascal Katharina Steindl Sarit Ravid Karin Weiss Alison M R Castle Melissa T Carter Louisa Kalsner Bert B A de Vries Bregje W van Bon Marijke R Wevers Rolph Pfundt Alexander P A Stegmann Bronwyn Kerr Helen M Kingston Kate E Chandler Willow Sheehan Abdallah F Elias Deepali N Shinde Meghan C Towne Nathaniel H Robin Dana Goodloe Adeline Vanderver Omar Sherbini Krista Bluske R Tanner Hagelstrom Caterina Zanus Flavio Faletra Luciana Musante Evangeline C Kurtz-Nelson Rachel K Earl Britt-Marie Anderlid Gilles Morin Marjon van Slegtenhorst Karin E M Diderich Alice S Brooks Joost Gribnau Ruben G Boers Teresa Robert Finestra Lauren B Carter Anita Rauch Paolo Gasparini Kym M Boycott Tahsin Stefan Barakat John M Graham Laurence Faivre Siddharth Banka Tianyun Wang Evan E Eichler Manuela Priolo Bruno Dallapiccola Lisenka E L M Vissers Bekim Sadikovic Daryl A Scott Jimmy Lloyd Holder Marco Tartaglia

Am J Hum Genet 2021 03 16;108(3):502-516. Epub 2021 Feb 16.

Genetics and Rare Disease Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address:

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008487PMC
March 2021

Selective interaction between phytomediated anionic silver nanoparticles and mercury leading to amalgam formation enables highly sensitive, colorimetric and memristor-based detection of mercury.

Sci Rep 2020 02 6;10(1):2037. Epub 2020 Feb 6.

School of Nanoscience and Biotechnology, Shivaji University, Vidyanagar, Kolhapur, Maharashtra, 416004, India.

Presently, nanotechnology is being foreseen to play an important role in developing analytical assays for the detection of pollutants like mercury (Hg). In this study, Kokum fruit mediated silver nanoparticles (AgNPs) were differentially centrifuged to prepare anionic, monodispersed AgNPs to develop a highly sensitive, colorimetric and memristor-based assay for detection of Hg in water samples. The investigation of the highly selective reaction between AgNPs and Hg using HAADF-STEM images and EDS spectrum indicated the amalgam formation through etching and under potential deposition which resulted in a visible color change from brown to colorless, change in SPR intensity and also change in memristive switching like property of AgNPs. The developed colorimetric assay detected Hg with a limit of detection (LOD) of 6.2 ppb and limit of quantification (LOQ) of 18.9 ppb and, quantitatively recovered Hg with good accuracy and precision (RSD < 2%). Further, the test of memristive switching like property of AgNPs demonstrated frequency-dependent shrinkage of I-V hysteresis loop indicating memristive switching like property. The test of the sensitivity of Hg detection was estimated to be 8.7 ppb as the LOD and 26.4 ppb as LOQ. Like the colorimetric assay, the memristor-based assay also recovered Hg with good accuracy and precision.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-58844-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005151PMC
February 2020

Selective and sensitive colorimetric detection of platinum using mediated optimally synthesized antibacterial silver nanoparticles.

Biotechnol Rep (Amst) 2020 Mar 22;25:e00404. Epub 2019 Nov 22.

School of Nanoscience and Biotechnology, Shivaji University, Kolhapur, Maharashtra, India.

In this work, was used for the optimum biogenic synthesis of antibacterial silver nanoparticles (AgNPs) which were applied for colorimetric detection of platinum ions (Pt). The optimum synthesis conditions were 2 mM AgNO pH 9 and incubation at 60 °C for 24 h. The FTIR spectra indicated that biomolecules such as amino acids, proteins or enzymes from were involved in the synthesis of AgNPs in the size range of 10-50 nm. Among the various metal ions tested and screened initially, the colloidal AgNPs probe-based colorimetric assay selectively detected Pt with 50 ppm as the limit of detection (LOD). The assay demonstrated in the present study quantitatively recovered Pt in the range of 70-150 % with good accuracy and precision. Further, the test of antibacterial activity of AgNPs alone, and in combination with ampicillin showed excellent activity against four of the six tested bacteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.btre.2019.e00404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906719PMC
March 2020

Immobilization of cellulase on iron tolerant Pseudomonas stutzeri biosynthesized photocatalytically active magnetic nanoparticles for increased thermal stability.

Mater Sci Eng C Mater Biol Appl 2020 Jan 6;106:110169. Epub 2019 Sep 6.

School of Nanoscience and Biotechnology, Shivaji University, Kolhapur, Maharashtra, India. Electronic address:

Bacteria mediated synthesis of magnetic nanoparticles (MNPs) for biotechnological applications is an important area of nanotechnology. This study demonstrates the use of iron tolerant bacterium for synthesis of MNPs for cellulase immobilization and photocatalytic activity. The enrichment, isolation, screening and molecular identification led to the selection of Pseudomonas stutzeri KDP_M2 with high degree of iron tolerance. The synthesis parameters such as 1 mM ferric quinate, pH 9 and 96 h static incubation were found optimum for maximum yield of 210 mg/L. The characterization using various techniques indicated that MNPs were Hematite (FeO) with particle size between 10 and 20 nm. Further, vibrating sample magnetometer and thermogravimetric analyses demonstrated the superparamagnetic nature with high thermal stability. The MNPs were found an excellent support for immobilization of industrially important cellulase with 96.5% binding efficiency. The immobilization which was confirmed by Fourier transform infrared spectroscopy indicated that immobilization did not reduce the cellulase activity, rather enhanced the thermal stability and operational temperature range of cellulase. The immobilized cellulase showed maximum cellulolytic activity at pH 4.6 and retained 80% activity upto 3rd cycle of reuse, therefore, can be utilized repeatedly at acidic conditions.The monitoring the photocatalytic activity showed rapid degradation of methyl violet and methylene blue within initial 10 min. of reaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msec.2019.110169DOI Listing
January 2020

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Authors:
Benjamin Cogné Sophie Ehresmann Eliane Beauregard-Lacroix Justine Rousseau Thomas Besnard Thomas Garcia Slavé Petrovski Shiri Avni Kirsty McWalter Patrick R Blackburn Stephan J Sanders Kévin Uguen Jacqueline Harris Julie S Cohen Moira Blyth Anna Lehman Jonathan Berg Mindy H Li Usha Kini Shelagh Joss Charlotte von der Lippe Christopher T Gordon Jennifer B Humberson Laurie Robak Daryl A Scott Vernon R Sutton Cara M Skraban Jennifer J Johnston Annapurna Poduri Magnus Nordenskjöld Vandana Shashi Erica H Gerkes Ernie M H F Bongers Christian Gilissen Yuri A Zarate Malin Kvarnung Kevin P Lally Peggy A Kulch Brina Daniels Andres Hernandez-Garcia Nicholas Stong Julie McGaughran Kyle Retterer Kristian Tveten Jennifer Sullivan Madeleine R Geisheker Asbjorg Stray-Pedersen Jennifer M Tarpinian Eric W Klee Julie C Sapp Jacob Zyskind Øystein L Holla Emma Bedoukian Francesca Filippini Anne Guimier Arnaud Picard Øyvind L Busk Jaya Punetha Rolph Pfundt Anna Lindstrand Ann Nordgren Fayth Kalb Megha Desai Ashley Harmon Ebanks Shalini N Jhangiani Tammie Dewan Zeynep H Coban Akdemir Aida Telegrafi Elaine H Zackai Amber Begtrup Xiaofei Song Annick Toutain Ingrid M Wentzensen Sylvie Odent Dominique Bonneau Xénia Latypova Wallid Deb Sylvia Redon Frédéric Bilan Marine Legendre Caitlin Troyer Kerri Whitlock Oana Caluseriu Marine I Murphree Pavel N Pichurin Katherine Agre Ralitza Gavrilova Tuula Rinne Meredith Park Catherine Shain Erin L Heinzen Rui Xiao Jeanne Amiel Stanislas Lyonnet Bertrand Isidor Leslie G Biesecker Dan Lowenstein Jennifer E Posey Anne-Sophie Denommé-Pichon Claude Férec Xiang-Jiao Yang Jill A Rosenfeld Brigitte Gilbert-Dussardier Séverine Audebert-Bellanger Richard Redon Holly A F Stessman Christoffer Nellaker Yaping Yang James R Lupski David B Goldstein Evan E Eichler Francois Bolduc Stéphane Bézieau Sébastien Küry Philippe M Campeau

Am J Hum Genet 2019 03 28;104(3):530-541. Epub 2019 Feb 28.

Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada. Electronic address:

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407527PMC
March 2019

An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex.

Nucleic Acids Res 2015 Mar 9;43(6):3100-13. Epub 2015 Mar 9.

Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

The MBD2-NuRD (Nucleosome Remodeling and Deacetylase) complex is an epigenetic reader of DNA methylation that regulates genes involved in normal development and neoplastic diseases. To delineate the architecture and functional interactions of the MBD2-NuRD complex, we previously solved the structures of MBD2 bound to methylated DNA and a coiled-coil interaction between MBD2 and p66α that recruits the CHD4 nucleosome remodeling protein to the complex. The work presented here identifies novel structural and functional features of a previously uncharacterized domain of MBD2 (MBD2IDR). Biophysical analyses show that the MBD2IDR is an intrinsically disordered region (IDR). However, despite this inherent disorder, MBD2IDR increases the overall binding affinity of MBD2 for methylated DNA. MBD2IDR also recruits the histone deacetylase core components (RbAp48, HDAC2 and MTA2) of NuRD through a critical contact region requiring two contiguous amino acid residues, Arg(286) and Leu(287). Mutating these residues abrogates interaction of MBD2 with the histone deacetylase core and impairs the ability of MBD2 to repress the methylated tumor suppressor gene PRSS8 in MDA-MB-435 breast cancer cells. These findings expand our knowledge of the multi-dimensional interactions of the MBD2-NuRD complex that govern its function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkv168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381075PMC
March 2015

Mi2β-mediated silencing of the fetal γ-globin gene in adult erythroid cells.

Blood 2013 Apr 26;121(17):3493-501. Epub 2013 Feb 26.

VCU Massey Cancer Center, Virginia Commonwealth University, 401 College St, Richmond, VA 23298, USA.

An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate β-type globin gene disorders such as sickle cell anemia and β-thalassemia through activation of the fetal γ-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD, play a role in γ-globin gene silencing, and Mi2β (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2β relieves γ-globin gene silencing in β-YAC transgenic murine chemical inducer of dimerization hematopoietic cells and in CD34(+) progenitor-derived human primary adult erythroid cells. We show that independent of MBD2-NuRD and GATA-1/FOG-1/NuRD, Mi2β binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for γ-globin gene silencing during β-type globin gene switching. Remarkably, <50% knockdown of Mi2β is sufficient to significantly induce γ-globin gene expression without disrupting erythroid differentiation of primary human CD34(+) progenitors. These results indicate that Mi2β is a potential target for therapeutic induction of fetal hemoglobin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2012-11-466227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637018PMC
April 2013

p66Alpha-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex.

Proc Natl Acad Sci U S A 2011 May 13;108(18):7487-92. Epub 2011 Apr 13.

Department of Human and Molecular Genetics, Institute of Structural Biology and Drug Design, Center for the Study of Biological Complexity, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.

Nucleosome remodeling complexes comprise several large families of chromatin modifiers that integrate multiple epigenetic control signals to play key roles in cell type-specific transcription regulation. We previously isolated a methyl-binding domain protein 2 (MBD2)-containing nucleosome remodeling and deacetylation (NuRD) complex from primary erythroid cells and showed that MBD2 contributes to DNA methylation-dependent embryonic and fetal β-type globin gene silencing during development in vivo. Here we present structural and biophysical details of the coiled-coil interaction between MBD2 and p66α, a critical component of the MBD2-NuRD complex. We show that enforced expression of the isolated p66α coiled-coil domain relieves MBD2-mediated globin gene silencing and that the expressed peptide interacts only with a subset of components of the MBD2-NuRD complex that does not include native p66α or Mi-2. These results demonstrate the central importance of the coiled-coil interaction and suggest that MBD2-dependent DNA methylation-driven gene silencing can be disrupted by selectively targeting this coiled-coil complex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1015341108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088629PMC
May 2011

Adopting a vegetarian meal plan. An option to consider.

Diabetes Self Manag 2010 Sep-Oct;27(5):27-8, 30-2, 34 passim

Amylin Pharmaceuticals, Inc., USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
November 2010

Managing highly insulin-resistant diabetes mellitus: weight loss approaches and medical management.

Postgrad Med 2010 Jan;122(1):163-71

University of Kentucky, 900 S. Limestone, Lexington, KY 40536, USA.

The prevalence of obesity and diabetes is epidemic. Severe insulin resistance (defined as the need for > or = 200 units of insulin per day to achieve glycemic control) is commonly seen with obesity and can complicate diabetes management. The management of patients with diabetes who have severe insulin resistance is difficult, and at times frustrating, and requires a multifaceted approach. Weight loss is the best treatment option, which can be a challenging task for patients to achieve and maintain. Medications that decrease insulin needs like metformin, thiazolidinediones, or pramlintide may help, but some patients also need high doses of insulin. This article reviews these different treatment options and provides practical advice on weight loss, use of insulin sensitizers, and use of U-500 insulin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3810/pgm.2010.01.2110DOI Listing
January 2010