Holly A. Feser Stessman, PhD

Department

Pharmacology and Neuroscience

Position

Associate Professor

Articles

• Frontiers in Genetics
  Jason Hulen/Holly A F Stessman, Dorothy Kenny, Rebecca Black, Jodi Hallgren, Kelley G Hammond, Eric C Bredahl, Rochelle N Wickramasekara, Peter W Abel Disruptive variants in lysine methyl transferase 5B (KMT5B/SUV4-20H1) have been identified as likely-pathogenic among humans with neurodevelopmental phenotypes including motor deficits (i.e., hypotonia and motor delay). However, the role that this enzyme plays in early motor development is largely unknown. Using a Kmt5b gene trap mouse model, we assessed neuromuscular strength, skeletal muscle weight (i.e., muscle mass), neuromuscular junction (NMJ) structure, and myofiber type, size, and distribution. Tests were performed over developmental time (postnatal days 17 and 44) to represent postnatal versus adult structures in slow- and fast-twitch muscle types. Prior to the onset of puberty, slow-twitch muscle weight was significantly reduced in heterozygous compared to wild-type males but not females. At the young adult stage, we identified decreased neuromuscular strength, decreased skeletal muscle weights (both slow- and fast-twitch), increased NMJ fragmentation (in slow-twitch muscle), and smaller myofibers in both sexes. We conclude that Kmt5b haploinsufficiency results in a skeletal muscle developmental deficit causing reduced muscle mass and body weight.
  13, p. 901228 2022
• Frontiers in Microbiology
  Jacob A Siedlik/Michael Belshan, Cynthia J Watson, Morgan A Raine, Anne V Cheng, Richard V Goering, Holly A F Stessman COVID-19 emerged at varying intervals in different regions of the United States in 2020. This report details the epidemiologic and genetic evolution of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first year of the epidemic in the state of Nebraska using data collected from the Creighton Catholic Health Initiatives (CHI) health system. Statistical modelling identified age, gender, and previous history of diabetes and/or stroke as significant risk factors associated with mortality in COVID-19 patients. In parallel, the viral genomes of over 1,000 samples were sequenced. The overall rate of viral variation in the population was 0.07 mutations/day. Genetically, the first 9 months of the outbreak, which include the initial outbreak, a small surge in August and a major outbreak in November 2020 were primarily characterized by B.1. lineage viruses. In early 2021, the United Kingdom variant (B.1.1.7 or alpha) quickly became the dominant variant. Notably, surveillance of non-consensus variants detected B.1.1.7 defining mutations months earlier in Fall 2020. This work provides insights into the regional variance and evolution of SARS-CoV-2 in the Nebraska region during the first year of the pandemic.
  13, p. 878342 2022
• Autism Research
  Wickramasekara, Rochelle N/Stessman, Holly A. F., Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in genetic studies of neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet, its role in the brain is not known. The goal of this work was to neurodevelopmentally characterize the effect(s) of KMT5B haploinsufficiency using a mouse model. A Kmt5b gene-trap mouse line was obtained from the Knockout Mouse Project. Wild type (WT) and heterozygous (HET) mice were subjected to a comprehensive neurodevelopmental test battery to assess reflexes, motor behavior, learning/memory, social behavior, repetitive movement, and common ASD comorbidities (obsessive compulsion, depression, and anxiety). Given the strong sex bias observed in the ASD patient population, we tested both a male and female cohort of animals and compared differences between genotypes and sexes. HET mice were significantly smaller than WT littermates starting at postnatal day 10 through young adulthood which was correlated with smaller brain size (i.e., microcephaly). This was more severe in males than females. HET male neonates also had delayed eye opening and significantly weaker reflexes than WT littermates. In young adults, significant differences between genotypes relative to anxiety, depression, fear, and extinction learning were observed. Interestingly, several sexually dimorphic differences were noted including increased repetitive grooming behavior in HET females and an increased latency to hot plate response in HET females versus a decreased latency in HET males. LAY SUMMARY: Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet its role in the brain is not known. Our study indicates that mice lacking one genomic copy of Kmt5b show deficits in neonatal reflexes, sociability, repetitive stress-induced grooming, changes in thermal pain sensing, decreased depression and anxiety, increased fear, slower extinction learning, and lower body weight, length, and brain size. Furthermore, several outcomes differed by sex, perhaps mirroring the sex bias in ASD. 2021
• Journal of Cancer Research and Therapeutic Oncology
  Christopher DeAngelo/Robin Farias-Eisner, Background: Endometriosis is complex, but identifying the novel biomarkers, inflammatory molecules, and genetic links holds the key to the enhanced detection, prediction and treatment of both endometriosis and endometriosis related malignant neoplasia. Here we review the literature relating to the specific molecular mechanism(s) mediating tumorigenesis arising within endometriosis. Methods: Guidance (e.g. Cochrane) and published studies were identified. The Published studies were identified through PubMed using the systematic review methods filter, and the authors’ topic knowledge. These data were reviewed to identify key and relevant articles to create a comprehensive review article to explore the molecular fingerprint associated with in endometriosis-driven tumorigenesis. Results: An important focus is the link between C3aR1, PGR, ER1, SOX-17 and other relevant gene expression profiles and endometriosis-driven tumorigenesis. Further studies should also focus on the combined use of CA-125 with HE-4, and the role for OVA1/MIA as clinically relevant diagnostic biomarkers in the prediction of endometriosis-driven tumorigenesis. Conclusions: Elucidating endometriosis’ molecular fingerprint is to understand the molecular mechanisms that drive the endometriosis-associated malignant phenotype. A better understanding of the predictive roles of these genes and the value of the biomarker proteins will allow for the derivation of unique molecular treatment algorithms to better serve our patients.
  8, p. 206 2020
• Reports (MDPI)
  Wickramasekara RN/ Stessman HAF, Schizophrenic Psychosis Symptoms in a Background of Mild-To-Moderate Carnitine Palmitoyltransferase II Deficiency: A Case Report
  3(4), p. 31 2020
• Cancer Research
  Duncan RM/Dolloff NG, ATF3 Coordinates Antitumor Synergy between Epigenetic Drugs and Protein Disulfide Isomerase Inhibitors
  80(16), p. 3279-3291 2020
• Autism Research
  Zohreh Talebizadeh, The AutGO Initiative: A Conceptual Framework for Developing Genetics‐Outcomes Research Hypotheses
  13(8), p. 1286-1299 2020
• Journal of Interprofessional Education & Practice
  Pope K/Doll JD, Clinician, Caregiver and Patient Perspectives of the Continuum of Care for Autism A Focus Group Study.
  19 2020
• Journal of Cancer Research and Clinical Oncology
  Su F/Farias-Eisner R, Bovine HDL and Dual Domain HDL-Mimetic Peptides Inhibit Tumor Development in Mice
  8(1), p. 101 2020
• Human Molecular Genetics
  Cheng H/Lyon GJ, Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15 2019
• American Journal of Human Genetics
  Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.
  104(3), p. 530-541 2019
• Biology
  Histone 4 Lysine 20 Methylation: A Case for Neurodevelopmental Disease.
  8(1) 2019
• Biological Psychiatry
  Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
  85(4), p. 287-297 2019
• Nature Genetics
  Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity.
  51(1), p. 106-116 2019
• American Journal of Human Genetics
  Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.
  102(5), p. 985-994 2018
• Autism Research and Treatment
  Associations between familial rates of psychiatric disorders and de novo genetic mutations in autism. 2017
• American Journal of Human Genetics
  De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.
  101(5), p. 768-88 2017
• Nature Neuroscience
  Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.
  20(8), p. 1043-51 2017
• Journal of Neurodevelopmental Disorders
  Exploring the heterogeneity of neural social indices for genetically-distinct etiologies of autism.
  9, p. 24 2017
• American Journal of Human Genetics
  De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.
  100(4), p. 689 2017
• Nature Genetics
  Targeted sequencing identifies 91 neurodevelopmental disorder risk genes with autism and developmental disability biases.
  49(4), p. 515-26 2017
• Nature Ecology and Evolution
  The evolution and population diversity of human-specific segmental duplication.
  1(3), p. 69 2017
• Methods in Molecular Biology
  Targeted capture and high-throughput sequencing using molecular inversion probes (MIPs).
  1492, p. 95-106 2017
• Autism Research
  Wickramasekara RN/ Stessman HAF, -0001

Presentations

• KMT5B is required for early motor development 2022
• Kmt5b is highly expressed in the developing brain and may regulate other known autism risk genes and processes 2021
• Characterization of KMT5B Haploinsufficiency in Mice Recapitulates Neurodevelopmental Disorder Phenotypes 2021
• "Behavioral and transcriptional analyses of Kmt5b haploinsufficient mice recapitulate human neurodevelopmental disorder phenotypes." Poster presentation. ASHG Annual Meeting, virtual due to COVID-19. 2020
• "Loss of Kmt5b results in structural changes at the skeletal muscle neuromuscular junction." Poster presentation. INSAR Annual Meeting, virtual due to COVID-19. 2020
• "Schizophrenic Psychosis Symptoms on a Background of Mild to Moderate Carnitine Palmitoyltransferase II Deficiency: A Case Report." Abstract for poster presentation. SFN Annual Meeting, Chicago, IL. 2019
• "Disruptive KMT5B variation alters growth and adhesion properties in an in vitro model." Abstract for poster presentation. ASHG Annual Meeting, Houston, TX. 2019
• "Disruptive KMT5B variation alters growth and adhesion properties in an in vitro model." SFARI Annual Fall Retreat, NY, NY. 2019
• "In vitro characterization of growth changes associated with ASD-linked genes." Oral presentation. SFARI Trainees Retreat, NY, NY. 2019
• Local AALAS (American Association for Laboratory Animal Sciences) branch: Spring Meeting. Title: Deciphering the role of KMT5B in neurodevelopment 2019
• Finding my passion: One scientist's story. Invited speaker for the 17th Summer Research Institute (SRI) Colloquium, Creighton University. 2017
• Creighton Psychiatry Grand Rounds -- Making Bench-to-Bedside Work: Success Stories in Autism. Co-presentation with Dr. Jen Gerdts (University of Washington) 2017
• The Identification of Novel Autism Risk Genes and Their Associated Phenotypes Using a Genotype-First Approach. Invited speaker for the 2017 INBRE Scholars Program, Creighton University. 2017
• Speaker panel: Building a phenotype: Discoveries of genetically distinct subtypes of ASD. "Targeted sequencing identifies 90 neurodevelopmental disorder risk genes with autism and developmental disability biases." Abstract for platform presentation. IMFAR/INSAR Annual Meeting, San Francisco, CA. 2017

State

• Identifying High-Risk Genetic Variation in Familial Breast & Ovarian Cancer

Other

• The Dr. George F. Haddix President’s Faculty Research Fund, Creighton University (Role: Co-I), Capturing the Gaps in Patients with Autism Through Collaborative Care (03/01/18 – 02/28/19)

Consulting

• PCORI Engagement/Educational Project (EAIN-3885)
  Consultant
  Children’s Mercy Kansas City - Zohreh Talebizadeh, PhD (PI)
  2017 - 2019