Markers and Models of Outcome in Galactosemia Öffentlichkeit
Sanders, Rebecca (2009)
Published
Abstract
Galactose metabolism occurs via the Leloir pathway, a highly
conserved series of reactions catalyzed by three enzymes:
galactokinase (GALK), galactose-1-phosphate uridylyltransferase
(GALT), and UDP-galactose-4'-epimerase (GALE). When dietary
galactose is insufficient, the Leloir pathway permits galactose
synthesis through GALE, which interconverts UDP-galactose and
UDP-glucose. In some species GALE also interconverts
UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. These four
UDP-sugars are essential for the biosynthesis of glycoproteins and
glycolipids.
Impairment of any Leloir pathway enzyme causes galactosemia.
Despite treatment with dietary galactose restriction, many
galactosemics with profound GALT or GALE deficiency develop
neurological complications. Additionally, 80-90% of women with
severe GALT impairment develop premature ovarian insufficiency
(POI). Understanding the pathophysiology of these complications has
been hindered by lack of a suitable animal model. This dissertation
presents a focused examination of the nature of
galactosemia-associated POI, and a more general exploration of GALE
deficiency using a novel D. melanogaster model.
Galactosemia-associated POI has been attributed to effects of
galactose and its metabolites in the ovary, or to dysfunction of
follicle-stimulating hormone (FSH) secondary to glycosylation
defects. To evaluate these explanations, we tested FSH and
anti-Mullerian hormone (AMH) in serum from galactosemic girls and
women. FSH bioactivity, a measure of the hormone's ability to
activate its receptor, was normal in our study population. However,
AMH abundance, a reflection of number and quality of ovarian
follicles, was strikingly low, even in girls younger than two years
old. These results indicate that POI in galactosemia is not caused
by ineffective FSH signaling, but by damage to the ovary in early
childhood or even prenatally.
To elucidate the pathophysiology of severe GALE deficiency, we have
generated the first whole animal model of GALE impairment. Our
studies in D. melanogaster confirm that total loss of GALE
is incompatible with life, and reveal that GALE is required
throughout development. Furthermore, we demonstrate that GALE
expression is only essential in certain tissues, and that
intermediate enzyme impairment permits survival but also confers
sensitivity to environmental galactose. This model of both profound
and intermediate GALE-deficiency recapitulates aspects of the human
disease and provides insight into the essential role of GALE in
tissues.
Table of Contents
Table of Contents
Chapter 1 Introduction
1.1 Galactose Metabolism
1.2 Galactosemia
1.3 Experimental Models Of Galactosemia
1.4 The Pathophysiology of Galactosemia
1.5 Summary
1.6 References
Chapter 2 Biomarkers Of Ovarian Function In Girls And
Women With Classic Galactosemia
2.1 Abstract
2.2 Introduction
2.3 Materials and Methods
2.4 Results
2.5 Discussion
2.6 References
Chapter 3 Role of GALE in Drosophila Development and
Homeostasis
3.1 Abstract
3.2 Introduction
3.3 Materials and Methods
3.4 Results
3.5 Discussion
3.6 References
Chapter 4 Conclusion
4.1 Summary
4.2 POI in Classical Galactosemia
4.3 GALE in Drosophila Development and
Homeostasis
4.4 References
Appendix Origins, Distribution, and Expression of the
Duarte-2 (D2) Allele of Galactose-1-P
Uridylyltransferase
A1.1 Abstract
A1.2 Introduction
A1.3 Materials and Methods
A1.4 Results
A1.5 Discussion
A1.6 References
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