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dc.contributor.authorDavid, Alessia
dc.description.abstractShort stature can be due to several causes, including genetically transmitted insensitivity to the action of growth hormone (GHI). In approximately 80% of referred patients, no aetiology can be identified and they are classified as having idiopathic short stature (ISS). The overall aim of this thesis was to identify and characterise the molecular mechanisms of GHI and ISS. The genetic analysis of a large GHI population identified several novel defects in the GH receptor (GHR), the signal transducer and activator of transcription (STAT5b) and the acid-labile subunit (lGFALS) genes and a genotype/phenotype relationship between GHR defects and GHI severity. In approximately 20% of GHI patients a GHR splice mutation was present. An in vitro splicing assay was developed and showed to accurately identify nucleotide changes resulting in aberrant mRNA splicing. Among the splice mutations, was the one leading to the activation of a GHR pseudoexon. This defect was found to be a common cause of GHI and a translational approach using antisense oligonucleotides showed to effectively correct in vitro the aberrant GHR mRNA splicing. During the course of the project an algorithm for the search of alternative exons and pseudoexons, was developed and allowed the identification of several potential regions, two of which were demonstrated to be expressed in human liver cDNA. Identification and analysis of GHI patients with ALS deficiency caused by IGF ALS defects and the observation of short stature in their heterozygote parents, led us to hypothesise the involvement of IGF ALS in the pathogenesis of ISS. Genetic analysis of a large ISS population showed the presence of single heterozygous IGF ALS defects in 9.6% of patients and in their short stature family members. Identification of the genetic defects responsible for growth failure can shed new light on the physiology of longitudinal growth and guide therapy in children with short stature.en_US
dc.titleMolecular mechanisms underlying growth hormone insensitivity and idiopathic short statureen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author

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  • Theses [3321]
    Theses Awarded by Queen Mary University of London

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