title: Pseudoexon activation as a novel mechanism for disease resulting in atypical growth-hormone insensitivity.
abstract: Inherited growth-hormone insensitivity (GHI) is a heterogeneous disorder that is often caused by mutations in the coding exons or flanking intronic sequences of the growth-hormone receptor gene (GHR). Here we describe a novel point mutation, in four children with GHI, that leads to activation of an intronic pseudoexon resulting in inclusion of an additional 108 nt between exons 6 and 7 in the majority of GHR transcripts. This mutation lies within the pseudoexon (A(-1)-->G(-1) at the 5' pseudoexon splice site) and, under in vitro splicing conditions, results in inclusion of the mutant pseudoexon, whereas the wild-type pseudoexon is skipped. The presence of the pseudoexon results in inclusion of an additional 36-amino acid sequence in a region of the receptor known to be involved in homo-dimerization, which is essential for signal transduction.
authors.affiliation: Department of Chemical Endocrinology, St. Bartholomew's Hospital, London EC1A 7BE, United Kingdom.
authors.forename: L A
authors.initials: LA
authors.lastname: Metherell
authors.forename: S A
authors.initials: SA
authors.lastname: Akker
authors.forename: P B
authors.initials: PB
authors.lastname: Munroe
authors.forename: S J
authors.initials: SJ
authors.lastname: Rose
authors.forename: M
authors.initials: M
authors.lastname: Caulfield
authors.forename: M O
authors.initials: MO
authors.lastname: Savage
authors.forename: S L
authors.initials: SL
authors.lastname: Chew
authors.forename: A J
authors.initials: AJ
authors.lastname: Clark
mesh_terms: D005260:Female; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D011544:Pseudogenes / Q000235:genetics*; D011986:Receptors, Somatotropin / Q000235:genetics*
chemical_list: D011986:Receptors, Somatotropin