Pseudoexon activation as a novel mechanism for disease resulting in atypical growth-hormone insensitivity

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.