| dc.description.abstract | Short 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 |
