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Theses

ÉTUDE DU RÔLE DU SÉLÉNIUM ET DE LA SÉLÉNOPROTÉINE N
DANS LES PATHOLOGIES MUSCULAIRES.

Abstract : Selenium was considered originally as a poison. It is only in the mid-fifties that the physiological significance of this trace element was correctly evaluated; identification of pathologies related to selenium deficiencies demonstrated its essential nutrient function in livestock and later in humans.
Biochemical studies identified selenocysteine as the major biological form of selenium in animals and bacteria. This particular amino acid is specifically incorporated into selenoproteins through a dedicated translation machinery.
Most of the known selenoproteins have not been attributed a function yet. Among them is selenoprotein N (SePN), a novel selenium containing protein identified in our laboratory in 1999.
In 2001, it was shown that several muscular disorders segregate with a locus containing SEPN1, the SePN encoding gene. These diseases are now collectively classified as SePN-related myopathies.

At the beginning of my PhD studies, little was known about selenoprotein N. To identify its function, several approaches were developed concomitantly.
First, I contributed to demonstrate that SePN is a 65kDa trans-membrane glycoprotein localized within the endoplasmic reticulum. Then, several successive approaches allowed characterization of SePN interacting partners in the membrane whose identification and further validation are underway.
In a second step, we developed two animal models for SePN related myopathies. Owing to an antisense strategy, it was shown that inhibition of SePN expression during zebrafish embryogenesis led to severe muscular defects and abnormal development. In parallel, taking advantage of the Cre-Lox system, we generated either the complete knock-out of the gene in mice or the conditional targeted disruption of the SEPN1 gene in muscle only. Both models showed no apparent defects. Histological studies, however, showed that muscles featured dystrophic muscular fiber patterns. In addition, we showed that SEPN1 knockout mice displayed increased sensitivity to induced oxidative stress. The functional exploration of these models will be pursued in collaboration with several groups.
Finally, another project that was tackled consisted in engineering a correction strategy based on the use of a modified tRNASec to force recognition of a mutated Sec codon in a RSMD1 patient with a homozygous point mutation. Successful experiments conducted in cultured cells opened the route toward a possible gene therapy for these patients.

Altogether, the studies will help obtaining a better insight into SePN function, especially in muscle physiology, as well as to increase our knowledge regarding selenium role in human health. The final aim of these studies is to develop targeted diagnostic and therapeutic tools that will derive from our predictive models.
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Contributor : Isabelle Martin <>
Submitted on : Monday, January 29, 2007 - 10:26:43 AM
Last modification on : Monday, October 19, 2020 - 11:08:55 AM
Long-term archiving on: : Tuesday, April 6, 2010 - 8:57:55 PM

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  • HAL Id : tel-00127081, version 1

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Citation

M. Rederstorff. ÉTUDE DU RÔLE DU SÉLÉNIUM ET DE LA SÉLÉNOPROTÉINE N
DANS LES PATHOLOGIES MUSCULAIRES.. Biochimie [q-bio.BM]. Université Louis Pasteur - Strasbourg I, 2006. Français. ⟨tel-00127081⟩

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