Genetics and Genomics Commons^™

Biallelic Missense Variants In Cog3 Cause A Congenital Disorder Of Glycosylation With Impairment Of Retrograde Vesicular Trafficking, Ruizhi Duan, Dana Marafi, Zhi-Jie Xia, Bobby G Ng, Reza Maroofian, Farhana Taher Sumya, Ahmed K Saad, Haowei Du, Jawid M Fatih, Jill V Hunter, Hasnaa M Elbendary, Shahid M Baig, Uzma Abdullah, Zafar Ali, Stephanie Efthymiou, David Murphy, Tadahiro Mitani, Marjorie A Withers, Shalini N Jhangiani, Zeynep Coban-Akdemir, Daniel G Calame, Davut Pehlivan, Richard A Gibbs, Jennifer E Posey, Henry Houlden, Vladimir V Lupashin, Maha S Zaki, Hudson H Freeze, James R Lupski

Faculty, Staff and Students Publications

Biallelic variants in genes for seven out of eight subunits of the conserved oligomeric Golgi complex (COG) are known to cause recessive congenital disorders of glycosylation (CDG) with variable clinical manifestations. COG3 encodes a constituent subunit of the COG complex that has not been associated with disease traits in humans. Herein, we report two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families that co-segregated with COG3-CDG presentations. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings. Biochemical analysis of serum transferrin from one family showed …

Utilization And Predictors Of Adjuvant Metformin For Children And Adolescents On Mixed Receptor Antagonists (Second-Generation Antipsychotics), Hua Chen, Ning Lyu, Wenyaw Chan, Austin De La Cruz, Chadi Calarge

Faculty, Staff and Student Publications

OBJECTIVE: to examine utilization and predictors of adjuvant metformin among pediatric recipients of second-generation antipsychotics (SGAs) (mixed receptor antagonist).

METHOD: This study used 2016-2021 data of a national electronic medical record database. Eligible participants were children aged 6 to 17 with a new SGA prescription for at least 90 days. Predictors of prescribing adjuvant metformin in general and to nonobese pediatric SGA recipients in particular were assessed using conditional logistic regression and logistic regression analyses, respectively.

RESULTS: Of 30,009 pediatric SGA recipients identified, 2.3% (n = 785) received adjuvant metformin. Among 597 participants with a body mass index z score …

Increasing Glutathione Levels By A Novel Posttranslational Mechanism Inhibits Neuronal Hyperexcitability, Ashwini Sri Hari, Rajeswari Banerji, Li-Ping Liang, Ruth E Fulton, Christopher Quoc Huynh, Timothy Fabisiak, Pallavi Bhuyan Mcelroy, James R Roede, Manisha Patel

Faculty, Staff and Students Publications

Glutathione (GSH) depletion, and impaired redox homeostasis have been observed in experimental animal models and patients with epilepsy. Pleiotropic strategies that elevate GSH levels via transcriptional regulation have been shown to significantly decrease oxidative stress and seizure frequency, increase seizure threshold, and rescue certain cognitive deficits. Whether elevation of GSH per se alters neuronal hyperexcitability remains unanswered. We previously showed that thiols such as dimercaprol (DMP) elevate GSH via post-translational activation of glutamate cysteine ligase (GCL), the rate limiting GSH biosynthetic enzyme. Here, we asked if elevation of cellular GSH by DMP altered neuronal hyperexcitability in-vitro and in-vivo. Treatment of …

Aso Silencing Of A Glycosyltransferase, Poglut1, Improves The Liver Phenotypes In Mouse Models Of Alagille Syndrome, Nima Niknejad, Duncan Fox, Jennifer L Burwinkel, Neda Zarrin-Khameh, Soomin Cho, Armand Soriano, Ashley E Cast, Mario F Lopez, Kari A Huppert, Frank Rigo, Stacey S Huppert, Paymaan Jafar-Nejad, Hamed Jafar-Nejad

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies and often leads to cholestatic liver disease. For example, in patients with Alagille syndrome (ALGS), which is a genetic disease primarily caused by mutations in jagged 1 ( JAG1) , BD paucity often results in severe cholestasis and liver damage. However, no mechanism-based therapy exists to restore the biliary system in ALGS or other diseases associated with BD paucity. Based on previous genetic observations, we investigated whether postnatal knockdown of the glycosyltransferase gene protein O -glucosyltransferase 1 ( Poglut1) can improve the ALGS liver phenotypes in …

Oral Follicle-Stimulating Hormone Receptor Agonist Affects Granulosa Cells Differently Than Recombinant Human Fsh, Joie Z Guner, Diana Monsivais, Henry Yu, Fabio Stossi, Hannah L Johnson, William E Gibbons, Martin M Matzuk, Stephen Palmer

Faculty, Staff and Students Publications

Objective:

To determine whether TOP5300, a novel oral follicle stimulating hormone receptor (FSHR) allosteric agonist, elicits a different cellular response than recombinant human FSH (rh-FSH) in human granulosa cells from in vitro fertilization patients.

Design:

Basic science research with a preclinical allosteric FSHR agonist.

Subjects:

Infertility patients at a single academic fertility clinic were recruited under an IRB-approved protocol. Primary granulosa cell cultures were established for 41 patients, of which 8 had normal ovarian reserve (NOR), 17 were of advanced reproductive age (ARA), 12 had a diagnosis of polycystic ovarian syndrome (PCOS), and 4 had a combination of diagnoses, such …

Health-Related Quality Of Life In A Systematically Assessed Cohort Of Children And Adults With Urea Cycle Disorders, Chaya N Murali, John R Barber, Robert Mccarter, Anqing Zhang, Natalie Gallant, Kara Simpson, Naghmeh Dorrani, Greta N Wilkening, Ron D Hays, Uta Lichter-Konecki, Members Of The Urea Cycle Disorders Consortium, Lindsay C Burrage, Sandesh C S Nagamani

Faculty, Staff and Students Publications

PURPOSE: Individuals with urea cycle disorders (UCDs) may develop recurrent hyperammonemia, episodic encephalopathy, and neurological sequelae which can impact Health-related Quality of Life (HRQoL). To date, there have been no systematic studies of HRQoL in people with UCDs.

METHODS: We reviewed HRQoL and clinical data for 190 children and 203 adults enrolled in a multicenter UCD natural history study. Physical and psychosocial HRQoL in people with UCDs were compared to HRQoL in healthy people and people with phenylketonuria (PKU) and diabetes mellitus. We assessed relationships between HRQoL, UCD diagnosis, and disease severity. Finally, we calculated sample sizes required to detect …

Multiple Light Signaling Pathways Control Solar Tracking In Sunflowers, Christopher J. Brooks, Hagop S. Atamian, Stacey L. Harmer

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Sunflowers are famous for their ability to track the sun throughout the day and then reorient at night to face east the following morning. This occurs by differential growth patterns, with the east sides of stems growing more during the day and the west sides of stems growing more at night. This process, termed heliotropism, is generally believed to be a specialized form of phototropism; however, the underlying mechanism is unknown. To better understand heliotropism, we compared gene expression patterns in plants undergoing phototropism in a controlled environment and in plants initiating and maintaining heliotropic growth in the field. We …

Yeast Crf1p: An Activator In Need Is An Activator Indeed, Sanjay Kumar

LSU Doctoral Dissertations

Ribosome biogenesis is an energetically costly process, and tight regulation is required for stoichiometric balance between components. This requires coordination of RNA polymerases I, II, and III. Lack of nutrients or the presence of stress leads to downregulation of ribosome biogenesis, a process for which mechanistic target of rapamycin complex I (mTORC1) is key. mTORC1 activity is communicated by means of specific transcription factors, and in yeast, which is a primary model system in which transcriptional coordination has been delineated, transcription factors involved in regulation of ribosomal protein genes include Fhl1p and its cofactors, Ifh1p and Crf1p. Ifh1p is an …

Book Review: Habitantes De La Obscuridad (Fauna Ibero-Balear De Las Cuevas) – Inhabitants Of The Darkness (Ibero-Baleric Fauna Of Caves), Oana Teodora Moldovan

International Journal of Speleology

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Simian Immunodeficiency Virus-Infected Rhesus Macaques With Aids Co-Develop Cardiovascular Pathology And Encephalitis, Kevin S. White, Joshua A. Walker, John Wang, Patrick Autissier, Andrew D. Miller, Nadia N. Abuelezan, Rachel Burrack, Qingsheng Li, Woong-Ki Kim, Kenneth C. Williams

Nebraska Center for Virology: Faculty Publications

Despite effective antiretroviral therapy, HIV co-morbidities remain where central nervous system (CNS) neurocognitive disorders and cardiovascular disease (CVD)-pathology that are linked with myeloid activation are most prevalent. Comorbidities such as neurocogntive dysfunction and cardiovascular disease (CVD) remain prevalent among people living with HIV. We sought to investigate if cardiac pathology (inflammation, fibrosis, cardiomyocyte damage) and CNS pathology (encephalitis) develop together during simian immunodeficiency virus (SIV) infection and if their co-development is linked with monocyte/ macrophage activation. We used a cohort of SIV-infected rhesus macaques with rapid AIDS and demonstrated that SIV encephalitis (SIVE) and CVD pathology occur together more frequently …

Multi-Tissue Epigenetic Analysis Identifies Distinct Associations Underlying Insulin Resistance And Alzheimer's Disease At Cpt1a Locus, Chloé Sarnowski, Tianxiao Huan, Yiyi Ma, Roby Joehanes, Alexa Beiser, Charles S Decarli, Nancy L Heard-Costa, Daniel Levy, Honghuang Lin, Ching-Ti Liu, Chunyu Liu, James B Meigs, Claudia L Satizabal, Jose C Florez, Marie-France Hivert, Josée Dupuis, Philip L De Jager, David A Bennett, Sudha Seshadri, Alanna C Morrison

Faculty, Staff and Student Publications

BACKGROUND: Insulin resistance (IR) is a major risk factor for Alzheimer's disease (AD) dementia. The mechanisms by which IR predisposes to AD are not well-understood. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus improving our understanding of the biological and regulatory mechanisms linking IR and AD.

METHODS: We conducted an epigenome-wide association study of IR, quantified using the homeostatic model assessment of IR (HOMA-IR) and adjusted for body mass index, in 3,167 participants from the Framingham Heart Study (FHS) without type 2 diabetes at the time of blood draw used for methylation measurement. We identified …

Genomic Insights Into The Mystery Of Mouse Mummies On The Summits Of Atacama Volcanoes, Jay F. Storz, Schuyler Liphardt, Marcial Quiroga-Carmona, Naim M. Bautista, Juan C. Opazo, Guillermo D’Elía, Jeffrey M. Good

Jay F. Storz Publications

Our understanding of the limits of animal life is continually revised by scientific exploration of extreme environments. Here we report the discovery of mummified cadavers of leaf-eared mice, Phyllotis vaccarum, from the summits of three different Andean volcanoes at elevations 6,029–6,233 m above sea level in the Puna de Atacama in Chile and Argentina. Such extreme elevations were previously assumed to be completely uninhabitable by mammals. In combination with a live-captured specimen of the same species from the nearby summit of Volcán Llullaillaco (6,739 m),¹ the summit mummies represent the highest altitude physical records of mammals in the …

Forest Composition Change And Biophysical Climate Feedbacks Across Boreal North America, Richard Massey, Brendan M. Rogers, Logan T. Berner, Sol Cooperdock, Michelle C. Mack, Xanthe J. Walker, Scott J. Goetz

Aspen Bibliography

Deciduous tree cover is expected to increase in North American boreal forests with climate warming and wildfire. This shift in composition has the potential to generate biophysical cooling via increased land surface albedo. Here we use Landsat-derived maps of continuous tree canopy cover and deciduous fractional composition to assess albedo change over recent decades. We find, on average, a small net decrease in deciduous fraction from 2000 to 2015 across boreal North America and from 1992 to 2015 across Canada, despite extensive fire disturbance that locally increased deciduous vegetation. We further find near-neutral net biophysical change in radiative forcing associated …

Identification Of Lipids And Cytokines In Plasma And Follicular Fluid Before And After Follicle-Stimulating Hormone Stimulation As Potential Markers For Follicular Maturation In Cattle, Alexandria P. Snider, Renata S. Gomes, Adam F. Summers, Sarah C. Tenley, Mohamed A. Abedal-Majed, Renee M. Mcfee, Jennifer R. Wood, John S. Davis, Andrea S. Cupp

Department of Animal Science: Faculty Publications

The process of follicle maturation leading to ovulation is a key milestone in female fertility. It is known that circulating lipids and cytokines play a role in the follicle’s ability to go through follicular maturation and the ovulatory processes. However, the specific mechanisms are not well understood. We posit that dysregulation of granulosa cells influences the ovarian environment, which tries to adapt by changing released lipids and cytokines to achieve follicular maturation. Eleven non-lactating adult females underwent estrus synchronization with two injections of PGF2 14 days apart. Daily blood samples were collected for 28 days to monitor steroid hormone production …

Further Refinement Of The Differentially Methylated Distant Lung-Specific Foxf1 Enhancer In A Neonate With Alveolar Capillary Dysplasia, Przemyslaw Szafranski, Rijutha P Garimella, Haresh Mani, Ryan Hartman, Gail Deutsch, Alan Silk, Alan Benheim, Paweł Stankiewicz

Faculty, Staff and Students Publications

Heterozygous SNVs or CNV deletions involving the FOXF1 gene, or its distant enhancer, are causative for 80-90% of cases of alveolar capillary dysplasia with misalignment of pulmonary veins. Recently, we proposed bimodal structure and parental functional dimorphism of the lung-specific FOXF1 enhancer, with Unit 1 having higher activity on the paternal chr16 and Unit 2 on the maternal chr16. Here, we describe a novel unusually sized pathogenic de novo copy-number variant deletion involving a portion of the FOXF1 enhancer on maternal chr16 that implies narrowing Unit 2 to an essential ~ 9-kb segment. Using a restrictase-based assay, we found that …

Co-Infection And Co-Localization Of Kaposi Sarcoma-Associated Herpesvirus And Epstein-Barr Virus In Hiv-Associated Kaposi Sarcoma: A Case Report, Peter Julius, Guobin Guobin, Stepfanie Siyumbwa, Jane Musumali, For Yue Tso, Owen Ngalamika, Trevor Kaile, Fred Maate, Phyllis Moonga, John T. West, Peter Angeletti, Charles Wood

Nebraska Center for Virology: Faculty Publications

Kaposi sarcoma (KS), a multifocal vascular neoplasm frequently observed in HIVpositive individuals, primarily affects the skin, mucous membranes, visceral organs, and lymph nodes. KS is associated primarily with Kaposi sarcomaassociated herpesvirus (KSHV) infection. In this case report, we present a rare occurrence of co-infection and co-localization of KSHV and Epstein-Barr virus (EBV) in KS arising from the conjunctiva, which, to our knowledge, has not been reported previously. Immunohistochemistry (IHC), DNA polymerase chain reaction (PCR), and EBV-encoded RNA in situ hybridization (EBER-ISH) were utilized to demonstrate the presence of KSHV and EBV infection in the ocular KS lesion. Nearly all KSHV-positive …

Biomechanical Origins Of Proprioceptor Feature Selectivity And Topographic Maps In The Drosophila Leg, Akira Mamiya, Anne Sustar, Igor Siwanowicz, Yanyan Qi, Tzu-Chiao Lu, Pralaksha Gurung, Chenghao Chen, Jasper S Phelps, Aaron T Kuan, Alexandra Pacureanu, Wei-Chung Allen Lee, Hongjie Li, Natasha Mhatre, John C Tuthill

Faculty, Staff and Students Publications

Our ability to sense and move our bodies relies on proprioceptors, sensory neurons that detect mechanical forces within the body. Different subtypes of proprioceptors detect different kinematic features, such as joint position, movement, and vibration, but the mechanisms that underlie proprioceptor feature selectivity remain poorly understood. Using single-nucleus RNA sequencing (RNA-seq), we found that proprioceptor subtypes in the Drosophila leg lack differential expression of mechanosensitive ion channels. However, anatomical reconstruction of the proprioceptors and connected tendons revealed major biomechanical differences between subtypes. We built a model of the proprioceptors and tendons that identified a biomechanical mechanism for joint angle selectivity …

Association Between Whole Blood-Derived Mitochondrial Dna Copy Number, Low-Density Lipoprotein Cholesterol, And Cardiovascular Disease Risk, Xue Liu, Xianbang Sun, Yuankai Zhang, Wenqing Jiang, Meng Lai, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Wei Zhao, Achilleas Pitsillides, Jeffrey Haessler, Yinan Zheng, Thomas W Blackwell, Jie Yao, Xiuqing Guo, Yong Qian, Bharat Thyagarajan, Nathan Pankratz, Stephen S Rich, Kent D Taylor, Patricia A Peyser, Susan R Heckbert, Sudha Seshadri, Eric Boerwinkle, Megan L Grove, Nicholas B Larson, Jennifer A Smith, Ramachandran S Vasan, Annette L Fitzpatrick, Myriam Fornage, Jun Ding, April P Carson, Goncalo Abecasis, Josée Dupuis, Alexander Reiner, Charles Kooperberg, Lifang Hou, Bruce M Psaty, James G Wilson, Daniel Levy, Jerome I Rotter, Joshua C Bis, Claudia L Satizabal, Dan E Arking, Chunyu Liu

Faculty, Staff and Student Publications

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia).

A Single-Dose Intramuscular Immunization Of Pigs With Lipid Nanoparticle Dna Vaccines Based On The Hemagglutinin Antigen Confers Complete Protection Against Challenge Infection With The Homologous Influenza Virus Strain, The N. Nguyen, Sushmita Kumari, Sarah Vitosh-Sillman, Jayeshbhai Chaudhari, Danh C. Lai, Hiep Vu

Nebraska Center for Virology: Faculty Publications

The Influenza A virus of swine (IAV-S) is highly prevalent and causes significant economic losses to swine producers. Due to the highly variable and rapidly evolving nature of the virus, it is critical to develop a safe and versatile vaccine platform that allows for frequent updates of the vaccine immunogens to cope with the emergence of new viral strains. The main objective of this study was to assess the feasibility of using lipid nanoparticles (LNPs) as nanocarriers for delivering DNA plasmid encoding the viral hemagglutinin (HA) gene in pigs. The intramuscular administration of a single dose of the LNP-DNA vaccines …

Associations Between Birth Defects And Childhood And Adolescent Germ Cell Tumors According To Sex, Histologic Subtype, And Site, Jeremy M Schraw, Pagna Sok, Tania A Desrosiers, Amanda E Janitz, Peter H Langlois, Mark A Canfield, A Lindsay Frazier, Sharon E Plon, Philip J Lupo, Jenny N Poynter

Faculty, Staff and Students Publications

BACKGROUND: Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics.

METHODS: Birth defect-GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population-based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and …