@phdthesis{01HGZK5DY9TYKKRJGH29ZKZR35,
  abstract     = {{Heritable connective tissue disorders are genetic disorders that affect the structure and function of
the building blocks of the body’s connective tissues. Individually, these disorders are rare diseases, but
collectively they form a significant health burden.
With the introduction of next-generation sequencing techniques over the past years, the genetic basis
of most of these disorders has been elucidated. Previous research on these disorders not only provided
important insights on the pathogenic mechanisms underlying these disorders, but also significantly
contributed to the knowledge on connective tissue biology and more common disease states such as
osteoarthritis and osteoporosis.
The Ehlers-Danlos syndromes (EDS) form a group of paradigm collagen-related heritable connective
disorders clinically characterized by joint hypermobility, skin hyperextensibility and variable degrees
of connective tissue fragility. The latest classification recognizes thirteen different EDS types with
defects in 20 different genes. Except for the molecularly unsolved hypermobile EDS type, a definite
diagnosis of EDS relies on the identification of a pathogenic defect in one of these EDS-related genes.
Although the genetic basis of most of the EDS types has been discovered, the molecular mechanisms
underlying and linking these different EDS types remain poorly understood. Moreover, the natural
history of these disorders is poorly documented and no evidence-based management guidelines exist.
Based on these unexplored clinical and molecular consequences of EDS, we formulated three research
objectives relevant to the clinical practice of EDS.
The first chapter aimed to provide an overview of the genetic spectrum associated with a clinical
presentation of classical Ehlers-Danlos syndrome (cEDS) and define the missing heritability. With
manuscript I, we reported the largest cohort of individuals with a clinical suspicion of cEDS ever
reported. The mutation detection rate was 82% indicating a significant remaining missing heritability.
The majority of the pathogenic defects were found in the genes encoding type v collagen, COL5A1 and
COL5A2. Pathogenic defects in other genes were found in 13% of the individuals, highlighting the
important phenotypical overlap between the different EDS types. Moreover, we provide the first
evidence for a genotype-phenotype correlation as defects in the COL5A2 gene often caused a more
severe phenotype. Manuscript II within this chapter is a collaborative study reporting a case series of
individuals who presented with phenotypes resembling cEDS in whom the COL1A1 c.934C>T,
p.(Arg312Cys) variant or glutamic acid to lysine (Glu-to-Lys) substitutions in the proα1(III)- collagen
chain were found. As only a handful individuals with these atypical variants has been reported, our
knowledge of the clinical spectrum associated with these genetic defects was limited. This
collaboration created the unique opportunity to systematically collect clinical data of affected
individuals enabled us to define some surveillance and management recommendations.
Despite being a major problem in daily clinical practice, pain in Ehlers-Danlos syndrome is poorly
studied. Our second objective was to characterize the pain signature and somatosensory profile in EDS
to increase our understanding of the mechanisms involved in the development and persistence of pain
in these individuals. We introduced this chapter with a summary of the few existing studies on pain in
both human EDS and animal models of EDS (manuscript III).
Manuscript IV describes a case-control study where we demonstrated partial defective central
modulation of pain in individuals with hypermobile EDS (hEDS) with increased temporal summation of
pain, and decreased exercise-induced hypoalgesia at the working muscle.
254
As there is no genetic marker for hEDS, its diagnosis is solely based on defined clinical criteria.
Therefore, there was an urgent need for clinical studies in individuals with molecular confirmed EDS
types. With Manuscript V, we describe the first study to systematically investigate pain and
somatosensory characteristics in a genetically defined HCTD. Individuals with cEDS report chronic pain
and worse health-related quality of life, and present altered somatosensory perception.
This chapter provides interesting insights on the possible role of the ECM in the development and
persistence of pain.
Finally, the third aim was to investigate the molecular consequences of kyphoscoliotic EDS (kEDS),
which can either be caused by deficiency of either LH1 (encoded by PLOD1) or FKBP22 (encoded by
FKBP14). Manuscript VI reports the clinical and molecular of 3 unrelated individuals with kEDS-FKBP14
and in Manuscript VII, 13 individuals with kEDS-PLOD1 are described. We provide an overview of the
clinical characteristics of all hitherto reported cases with kEDS-PLOD1 and kEDS-FKBP14, and highlight
some phenotypical differences between both disorders. Using patient-derived skin fibroblast cultures,
we provide the first evidence for intracellular retention of types III and VI collagen inEDS‐FKBP14, and
show upregulation of PLOD2 and lower protein levels of SC65 in individuals with kEDS-PLOD1.
Moreover, with evidence for higher protein levels of FKBP22, and higher expression of FKBP14 in
individuals with kEDS-PLOD1, we provide a first possible molecular link between kEDS-FKBP14 and
kEDS-PLOD1.
In summary, this dissertation made some significant contributions to the field of EDS and our
understanding of the ECM. Our findings laid the foundations for future research and paved the way
towards improved management of these disorders.}},
  author       = {{Colman, Marlies}},
  language     = {{eng}},
  pages        = {{293}},
  publisher    = {{Ghent University. Faculty of Medicine and Health Sciences}},
  school       = {{Ghent University}},
  title        = {{Unexplored clinical and molecular consequences of the Ehlers-Danlos syndromes}},
  year         = {{2023}},
}