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Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons

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Activation Of Target Gene Expression In Neurons By The C. Elegans Rfx Transcription Factor, Daf-19, Katherine P. Mueller 2016 Lawrence University

Activation Of Target Gene Expression In Neurons By The C. Elegans Rfx Transcription Factor, Daf-19, Katherine P. Mueller

Lawrence University Honors Projects

DAF-19, the only RFX transcription factor found in C. elegans, is required for the formation of neuronal sensory cilia. Four isoforms of the DAF-19 protein have been reported, and the m86 nonsense (null) mutation affecting all four isoforms has been shown to prevent cilia formation. Transcriptome analyses employing microarrays of L1 and adult stage worms were completed using RNA from daf-19(m86) worms and an isogenic wild type strain to identify additional putative DAF-19 target genes. Using transcriptional fusions with GFP, we compared the expression patterns of several potential gene targets using fluorescence confocal microscopy. Expression patterns were characterized in ...


Sustained Expression With Partial Correction Of Neutrophil Defects 5 Years After Intramuscular Raav1 Gene Therapy For Alpha-1 Antitrypsin Deficiency, Terence R. Flotte, Christian Mueller, Gwladys Gernoux, Alisha Gruntman, Jeffrey D. Chulay, David R. Knop, Noel G. McElvaney, Martha Campbell-Thompson, James M. Wilson 2016 University of Massachusetts Medical School

Sustained Expression With Partial Correction Of Neutrophil Defects 5 Years After Intramuscular Raav1 Gene Therapy For Alpha-1 Antitrypsin Deficiency, Terence R. Flotte, Christian Mueller, Gwladys Gernoux, Alisha Gruntman, Jeffrey D. Chulay, David R. Knop, Noel G. Mcelvaney, Martha Campbell-Thompson, James M. Wilson

UMass Center for Clinical and Translational Science Research Retreat

Alpha-1 antitrypsin (AAT) deficiency is a common monogenic disorder resulting in emphysema, which is currently treated with weekly infusions of protein replacement. We previously reported achieving plasma wild-type (M) AAT concentrations at 2.5-3.8% of the therapeutic level at 1 year after intramuscular (IM) administration of 6×1012vg/kg of a recombinant adeno-associated virus serotype 1 (rAAV1)-AAT vector in AAT-deficient patients, with an associated regulatory T cell (Treg) response to AAV1 capsid epitopes in the absence of any exogenous immune suppression. Here, we report sustained expression at greater than 2% of the therapeutic level for 5 years after ...


Airway Smooth Muscle Pathology In Pompe Disease, Lang Xiong, Allison M. Keeler, Donghai Lui, Kaitlyn Desrochers, Ronghua Zhuge, Mai K. Elmallah 2016 University of Massachusetts Medical School

Airway Smooth Muscle Pathology In Pompe Disease, Lang Xiong, Allison M. Keeler, Donghai Lui, Kaitlyn Desrochers, Ronghua Zhuge, Mai K. Elmallah

UMass Center for Clinical and Translational Science Research Retreat

Pompe disease is a rare autosomal recessive disease which results from a deficiency of acid α-glucosidase (GAA) - an enzyme that degrades lysosomal glycogen. Patients with Pompe disease develop intra-lysosomal accumulation of glycogen in multiple tissues including skeletal muscle, CNS and smooth muscle.

Pulmonary dysfunction is a hallmark of Pompe disease and has classically been attributed to muscle weakness and CNS neuropathology. However, the potential role of respiratory smooth muscles in the respiratory pathology is unknown. Therefore we postulated that GAA deficiency results in airway smooth muscle glycogen accumulation that leads to airway smooth muscle dysfunction.

Using the Pompe mouse model ...


Characterization Of Respiratory Phenotype In Very Long-Chain Acyl-Coa Dehydrogenase Deficient Mice., Allison M. Keeler, Kaitlyn Desrochers, Mai K. Elmallah 2016 University of Massachusetts Medical School

Characterization Of Respiratory Phenotype In Very Long-Chain Acyl-Coa Dehydrogenase Deficient Mice., Allison M. Keeler, Kaitlyn Desrochers, Mai K. Elmallah

UMass Center for Clinical and Translational Science Research Retreat

Rationale: Very Long-chain Acyl-CoA dehydrogenase (VLCAD) deficiency the most common inherited long-chain fatty acid disorder. The VLCAD enzyme catalyzes the first step of mitochondrial fatty acid oxidation and loss of the enzyme results in energy deficiency as well as accumulation of long chain fatty acids. Recently, a related enzyme, Long-chain Acyl-CoA dehydrogensase (LCAD), which unlike VLCAD is not highly expressed in metabolic tissues like liver, heart and skeletal muscle, was found to be expressed in the lung and surfactant and lung dysfunction were observed in LCAD deficient mice. Respiratory distress syndrome has been described in other fatty acid oxidation disorders ...


Translating Dosage Compensation To Trisomy 21, Jun Jiang, Yuanchun Jing, Gregory J. Cost, Jen-Chieh Chiang, Heather J. Kolpa, Allison M. Cotton, Dawn M. Carone, Benjamin R. Carone, Meg Byron, Philip D. Gregory, Carolyn J. Brown, Fyodor D. Urnov, Lisa L. Hall, Jeanne B. Lawrence 2016 University of Massachusetts Medical School

Translating Dosage Compensation To Trisomy 21, Jun Jiang, Yuanchun Jing, Gregory J. Cost, Jen-Chieh Chiang, Heather J. Kolpa, Allison M. Cotton, Dawn M. Carone, Benjamin R. Carone, Meg Byron, Philip D. Gregory, Carolyn J. Brown, Fyodor D. Urnov, Lisa L. Hall, Jeanne B. Lawrence

UMass Center for Clinical and Translational Science Research Retreat

Down syndrome is the leading genetic cause of intellectual disabilities, occurring in 1 out of 700 live births. Given that Down syndrome is caused by an extra copy of chromosome 21 that involves over-expression of 400 genes across a whole chromosome, it precludes any possibility of a genetic therapy. Our lab has long studied the natural dosage compensation mechanism for X chromosome inactivation. To “dosage compensate” X-linked genes between females and males, the X-linked XIST gene produces a large non-coding RNA that silences one of the two X chromosomes in female cells. The initial motivation of this study was to ...


Phylogenetic Analysis Of Human Cytomegalovirus Pus27 And Pus28: Ascertaining An Independent Or Linked Evolutionary History, Jessica A. Scarborough 2016 University of San Francisco

Phylogenetic Analysis Of Human Cytomegalovirus Pus27 And Pus28: Ascertaining An Independent Or Linked Evolutionary History, Jessica A. Scarborough

Undergraduate Honors Theses

Human cytomegalovirus (HCMV) is a widespread pathogen that is particularly skilled at evading immune detection and defense mechanisms, largely due to extensive co-evolution with its host’s immune system. One aspect of this co-evolution involves the acquisition of four virally encoded GPCR chemokine receptor homologs, products of the US27, US28, UL33 and UL78 genes. G protein-coupled receptors (GPCR) are the largest family of cell surface proteins, found in organisms from yeast to humans. In this research, phylogenetic analysis was used to investigate the origins of the US27 and US28 genes, which are adjacent in the viral genome. The results indicate ...


Virus-Host Co-Evolution: Determining The Origin Of Human Cytomegalovirus Us27 And Us28, Jessica A. Scarborough, Juliet Spencer, John Paul 2016 University of San Francisco

Virus-Host Co-Evolution: Determining The Origin Of Human Cytomegalovirus Us27 And Us28, Jessica A. Scarborough, Juliet Spencer, John Paul

Creative Activity and Research Day - CARD

G protein-coupled receptors (GPCR) are the largest family of cell surface proteins, found in organisms from yeast to humans. Human cytomegalovirus (HCMV) is a widespread pathogen that is particularly skilled at evading immune detection and defense mechanisms, largely due to extensive co-evolution with its host’s immune system. One aspect of this co-evolution involves the acquisition of four virally encoded GPCR homologs: US27, US28, UL33 and UL78. In this research, phylogenetic analysis was used to investigate the origins of the US27 and US28 genes, which are adjacent in the viral genome. The results indicate that both US27 and US28 share ...


Dnah6 And Its Interactions With Pcd Genes In Heterotaxy And Primary Ciliary Dyskinesia, You Li, Hisato Yagi, Gregory M. Hendricks, Gregory J. Pazour, Cecilia W. Lo 2016 University of Pittsburgh

Dnah6 And Its Interactions With Pcd Genes In Heterotaxy And Primary Ciliary Dyskinesia, You Li, Hisato Yagi, Gregory M. Hendricks, Gregory J. Pazour, Cecilia W. Lo

Open Access Articles

Heterotaxy, a birth defect involving left-right patterning defects, and primary ciliary dyskinesia (PCD), a sinopulmonary disease with dyskinetic/immotile cilia in the airway are seemingly disparate diseases. However, they have an overlapping genetic etiology involving mutations in cilia genes, a reflection of the common requirement for motile cilia in left-right patterning and airway clearance. While PCD is a monogenic recessive disorder, heterotaxy has a more complex, largely non-monogenic etiology. In this study, we show mutations in the novel dynein gene DNAH6 can cause heterotaxy and ciliary dysfunction similar to PCD. We provide the first evidence that trans-heterozygous interactions between DNAH6 ...


Geographic Distribution Of Infant Death During Birth Hospitalization And Maternal Group B Streptococcus Colonization: Eastern Wisconsin, Jessica Kram, Dennis Baumgardner, Kiley Bernhard, Melissa Lemke 2016 Center for Urban Population Health, Aurora Health Care

Geographic Distribution Of Infant Death During Birth Hospitalization And Maternal Group B Streptococcus Colonization: Eastern Wisconsin, Jessica Kram, Dennis Baumgardner, Kiley Bernhard, Melissa Lemke

Dennis Baumgardner

Background: Neonatal death rate in the United States is 4/1,000 live births; infant death rate is 6/1,000. Group B Streptococcus (GBS) may be transmitted from a colonized mother (rates vary from 15% to 35%) to the newborn during a vaginal delivery, and may contribute to neonatal death. Purpose: To explore the geographic distribution and associated risk factors for maternal GBS colonization and infant death prior to discharge in eastern Wisconsin births. Methods: Retrospective study of institutional data from PeriData.net, a comprehensive birth registry, utilizing data from 2007 through 2013 at all Aurora medical centers. Categorical ...


Maternal Anxiety Associated With Newborn Hearing Screening, Stephen J. Tueller, Karl R. White 2016 RTI International

Maternal Anxiety Associated With Newborn Hearing Screening, Stephen J. Tueller, Karl R. White

Journal of Early Hearing Detection and Intervention

The purpose of this study was to determine if newborn hearing screening increases maternal anxiety. Mothers whose infants were screened for hearing were asked how worried they were prior to hospital discharge and again six weeks later. They were also asked if they were more concerned about their baby’s hearing than they were about other aspects of the infant’s health and behavior.

Results showed that mothers worried as much or more about many other aspects of their infants’ health and behavior as about hearing. Mothers whose infants had a false positive screening result were initially more worried about ...


Posterior Lenticonus In The Dog, Gustavo Aguirre, Stephen Bistner 2016 University of Pennsylvania

Posterior Lenticonus In The Dog, Gustavo Aguirre, Stephen Bistner

Gustavo D. Aguirre, VMD, PhD

Posterior lenticonus is a congenital defect of the posterior lenticular surface. The posterior cortical and capsular regions of the lens have a circumscribed conelike or globular protrusion of variable size. Opacities may be present in the region of the conus. The defect has been reported in man, rabbits, calves and mice. This report documents 2 cases in unrelated dogs. The possible mechanism for the formation of this defect is discussed.


Canine Rd3 Mutation Establishes Rod-Cone Dysplasia Type 2 (Rcd2) As Ortholog Of Human And Murine Rd3, Anna Kukekova, Orly Goldstein, Jennifer Johnson, Malcolm Richardson, Susan Pearce-Kelling, Anand Swaroop, James Friedman, Gustavo Aguirre, Gregory Acland 2016 University of Pennsylvania

Canine Rd3 Mutation Establishes Rod-Cone Dysplasia Type 2 (Rcd2) As Ortholog Of Human And Murine Rd3, Anna Kukekova, Orly Goldstein, Jennifer Johnson, Malcolm Richardson, Susan Pearce-Kelling, Anand Swaroop, James Friedman, Gustavo Aguirre, Gregory Acland

Gustavo D. Aguirre, VMD, PhD

Rod-cone dysplasia type 2 (rcd2) is an autosomal recessive disorder that segregates in collie dogs. Linkage disequilibrium and meiotic linkage mapping were combined to take advantage of population structure within this breed and to fine map rcd2 to a 230-kb candidate region that included the gene C1orf36 responsible for human and murine rd3, and within which all affected dogs were homozygous for one haplotype. In one of three identified canine retinal RD3 splice variants, an insertion was found that cosegregates with rcd2 and is predicted to alter the last 61 codons of the normal open reading frame and further extend ...


Col9a2 And Col9a3 Mutations In Canine Autosomal Recessive Oculoskeletal Dysplasia, Orly Goldstein, Richard Guyon, Anna Kukekova, Tatyana Kuznetsova, Susan Pearce-Kelling, Jennifer Johnson, Gustavo Aguirre, Gregory Acland 2016 University of Pennsylvania

Col9a2 And Col9a3 Mutations In Canine Autosomal Recessive Oculoskeletal Dysplasia, Orly Goldstein, Richard Guyon, Anna Kukekova, Tatyana Kuznetsova, Susan Pearce-Kelling, Jennifer Johnson, Gustavo Aguirre, Gregory Acland

Gustavo D. Aguirre, VMD, PhD

Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in ...


Canine And Human Visual Cortex Intact And Responsive Despite Early Retinal Blindness From Rpe65 Mutation, Geoffrey Aguirre, András Komáromy, Artur Cideciyan, David Brainard, Tomas Aleman, Alejandro Roman, Brian Avants, James Gee, Marc Korczykowski, William Hauswirth, Gregory Acland, Gustavo Aguirre, Samuel Jacobson 2016 University of Pennsylvania

Canine And Human Visual Cortex Intact And Responsive Despite Early Retinal Blindness From Rpe65 Mutation, Geoffrey Aguirre, András Komáromy, Artur Cideciyan, David Brainard, Tomas Aleman, Alejandro Roman, Brian Avants, James Gee, Marc Korczykowski, William Hauswirth, Gregory Acland, Gustavo Aguirre, Samuel Jacobson

Gustavo D. Aguirre, VMD, PhD

Background RPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans ...


Cloning Of Canine Galactokinase (Galk1) And Evaluation As A Candidate Gene For Hereditary Cataracts In Labrador Retrievers, Duska Sidjanin, John McElwee, Brian Miller, Gustavo Aguirre 2016 University of Pennsylvania

Cloning Of Canine Galactokinase (Galk1) And Evaluation As A Candidate Gene For Hereditary Cataracts In Labrador Retrievers, Duska Sidjanin, John Mcelwee, Brian Miller, Gustavo Aguirre

Gustavo D. Aguirre, VMD, PhD

We identified a pedigree of Labrador retrievers (LR) that develop hereditary cataracts between 6 and 18 months of age. In humans, galactokinase deficiency is an autosomal recessive disorder characterized by juvenile onset of cataracts.1 In order to evaluate GALK1 as a candidate gene, we cloned and sequenced the canine GALK1 gene and tested a single nucleotide polymorphism (SNP) in the gene for segregation with cataracts in the LR pedigree.


Canine Multifocal Retinopathy In The Australian Shepherd: A Case Report, Ingo Hoffmann, Karina Guziewicz, Barbara Zangerl, Gustavo Aguirre, Christian Mardin 2016 University of Pennsylvania

Canine Multifocal Retinopathy In The Australian Shepherd: A Case Report, Ingo Hoffmann, Karina Guziewicz, Barbara Zangerl, Gustavo Aguirre, Christian Mardin

Gustavo D. Aguirre, VMD, PhD

A 1-year-old Australian Shepherd (AS) was presented for a routine hereditary eye examination. During the examination multiple raised, brown to orange lesions were noted in the fundus, which could not be attributed to a known retinal disease in this breed. As they clinically most closely resembled canine multifocal retinopathy (cmr) and no indication of an acquired condition was found, genetic tests for BEST1 gene mutations were performed. These showed the dog to be homozygous for the cmr1 (C73T/R25X) gene defect. Furthermore, ultrasound (US), electroretinography (ERG), and optical coherence tomography were performed, confirming changes typical for cmr. Subsequently, the AS ...


Blinded By The Light: Retinal Phototoxicity In The Context Of Safety Studies, Maria Cristina De Vera Mudry, Sven Kronenberg, Shun-ichiro Komatsu, Gustavo Aguirre 2016 University of Pennsylvania

Blinded By The Light: Retinal Phototoxicity In The Context Of Safety Studies, Maria Cristina De Vera Mudry, Sven Kronenberg, Shun-Ichiro Komatsu, Gustavo Aguirre

Gustavo D. Aguirre, VMD, PhD

No abstract provided.


The Heli-Case Of The Missing Wrn Gene, Lisa Jeziorny, Lindsey McCurdy, Katie Michael, Jennifer Riddle, Kim Silvers 2016 Lake Forest College

The Heli-Case Of The Missing Wrn Gene, Lisa Jeziorny, Lindsey Mccurdy, Katie Michael, Jennifer Riddle, Kim Silvers

Eukaryon

Werner Syndrome is an autosomal recessive disease characterized by genomic instability, accelerated telomere shortening, and premature aging. Also, Werner Syndrome patients experience increased cancer rates, believed to be directly related to the lack of interaction between the WRN gene and tumor suppressor gene p53. The WRN gene consists of three identical molecules and has both exonuclease and helicase activity, which work together in opposite directions. WRN has been shown to stimulate polymerase â, needed in DNA repair. WRN helicase activity can also bind and degrade G-quadruplexes, which inhibit transcription. Studies show that the tumor suppressor gene p53 co-localizes with WRN ...


Retrospective Frames Of Disability: Themes Derived From Parents Of Children Who Grew Up With Congenital Disability, Sheryl L. Holt 2016 University of Kentucky

Retrospective Frames Of Disability: Themes Derived From Parents Of Children Who Grew Up With Congenital Disability, Sheryl L. Holt

Theses and Dissertations--Rehabilitation Sciences

Introduction: For children born with physical disabilities, the perspectives and actions of their parents prove significant to their childhood developmental outcomes clinically, educationally, socially, and with regard to community participation. The lived world and perceptions of parents who have children with disabilities however is not well investigated. This study sought to understand parents’ framing of theirs and their children’s disability experiences. Family systems together with family systems intervention models, and disability theory were used to provide structure to interview instrumentation and subsequent analysis. Child-centered and ecologic influences were also used to track the transformative processes over time that infuses ...


Manic Symptoms And Behavioral Dysregulation In Youth With Velocardiofacial Syndrome (22q11.2 Deletion Syndrome)., Alka Aneja, Wanda Fremont, Kevin Antshel, Stephen Faraone, Nuria AbdulSabur, Anne Marie Higgins, Robert Shprintzen, Wendy Kates 2015 Sacred Heart University

Manic Symptoms And Behavioral Dysregulation In Youth With Velocardiofacial Syndrome (22q11.2 Deletion Syndrome)., Alka Aneja, Wanda Fremont, Kevin Antshel, Stephen Faraone, Nuria Abdulsabur, Anne Marie Higgins, Robert Shprintzen, Wendy Kates

Robert J. Shprintzen

Mania and bipolar disorder have been reported in adolescents and adults with velocardiofacial syndrome (VCFS; also known as 22q11.2 deletion syndrome). Children with VCFS have a high prevalence of attention-deficit/hyperactivity disorder (ADHD), which may constitute a risk factor for the eventual development of bipolar disorder in this population. Therefore, we sought to determine whether children with VCFS exhibit more manic symptoms than community controls that also may have learning disorders and ADHD. The study population consisted of 86 children with VCFS and 36 community controls from ages 9 to 15 years, using measures of Young Mania Rating Scale-Parent ...


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