Date of Award

Spring 2026

Embargo Period

2-19-2028

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Regenerative Medicine and Cell Biology

First Advisor

Russell A. Norris

Second Advisor

Robin Muise-Helmericks

Third Advisor

Mindy Engevik

Fourth Advisor

Carol Feghali-Bostwick

Fifth Advisor

Paula Ramos

Abstract

The Ehlers-Danlos syndromes (EDS) comprise a group of heritable disorders characterized by disruptions in extracellular matrix (ECM) biology that give rise to complex, multisystem disease. While pathogenic variants have been identified for most EDS subtypes, the mechanisms linking genetic variation to tissue-level pathology and clinical expression remain poorly understood. This dissertation addresses these gaps through an integrated approach combining experimental models, histological and single-nucleus RNA sequencing analyses, clinical phenotyping, and genome-wide association studies (GWAS) leveraging a large patient registry to connect molecular and cellular mechanisms with human disease risk and phenotypic complexity.

To better understand the EDS subtypes, a comprehensive mouse repository was generated using CRISPR/Cas9-engineered alleles corresponding to pathogenic variants across all 14 EDS subtypes. To examine the molecular mechanisms of dermatosparaxis EDS (dEDS), an Adamts2Q226* knock-in mouse model was used to test how Adamts2 mutation affects collagen maturation and ECM organization. These studies show that Adamts2 mutation disrupts collagen processing, alters ECM architecture, and reshapes fibroblast transcriptional profiles, establishing fibroblast-driven ECM disorganization as a central pathogenic mechanism in dEDS.

To bridge ECM-centered mechanisms to human disease, a large hypermobile EDS (hEDS) cohort was evaluated for musculoskeletal, autonomic, gastrointestinal, immune, neurological, and gynecologic manifestations using a self-reported survey. These analyses reveal multisystem involvement in hEDS, highlighting that the condition extends beyond joint hypermobility to encompass significant neuroimmune and gastrointestinal dysfunction. In parallel, a study of pineal cyst morphology and symptomatology in a non-EDS population provides an independent lens on how connective tissue biology may influence intracranial structure and neurological outcomes.

Finally, to define the genetic architecture underlying hEDS, a GWAS was performed that identifies common genetic variants and pathways associated with hEDS risk, providing strong evidence that hEDS is a polygenic disorder. Implicated loci converge on fibroblast function, ECM regulation, immune signaling, and pain pathways, offering a unifying genetic framework for the multisystem phenotypes observed clinically.

Collectively, this dissertation establishes new experimental models, clarifies patterns of human phenotypic complexity, and generates testable mechanistic and genetic hypotheses that advance understanding of EDS pathophysiology and inform future efforts toward improved diagnostics and targeted therapies.

Rights

Copyright is held by the author. All rights reserved.

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