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.

An Apparent Pseudo-Exon Acts both as an Alternative Exon That Leads to Nonsense-Mediated Decay and as a Zero-Length Exon

“…Moreover, this property was conserved with all tested TM pseudo-exons (human, chimp, rat, mouse, and dog) clustering together. We also plotted two other pseudo-exons that are activated in human disease: one from the ATM gene (27) and one from the GHR gene (25). Although both of these had a relatively low ESS count, they also had a low ESE content and, in contrast to the TM pseudo-exon, did not lie in a region that was enriched in real exons.…”

Biological Determinants of Responsiveness to Growth Hormone: Pharmacogenomics and Personalized Medicine

“…Expression Failure [20,21] Inherited GHI is a heterogeneous disorder that is often caused by mutations in the coding exons or flanking intronic sequences of the GHR gene. In 4 children with GHI, Metherell et al [21] described a novel point mutation that led 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.…”

“…In 4 children with GHI, Metherell et al [21] described a novel point mutation that led 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 5Ј pseudoexon splice site] and, under in vitro splicing conditions, results in inclusion of the mutant pseudoexon, whereas the wild-type pseudoexon is skipped.…”

“…This mutation lies within the pseudoexon [A(-1)→G(-1) at the 5Ј 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 previously alleged to be involved in homodimerization, which may be essential for signal transduction [21]. Based on functional studies, Maamra et al [20] have shown that this elongated GHR remained trapped around the nucleus and is therefore poorly expressed at the cell membrane, reflecting a trafficking defect and, thus, reduced downstream signaling.…”

An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease

“…The first pseudoexon mutation leading to disease was identified in the ATM gene in an individual with familial ataxia telangiectasia (McConville et al 1996). Since then, pseudoexon mutations have been identified in GHR (Metherell et al 2001;David et al 2007), DMD (TufferyGiraud et al 2003;Eng et al 2004;Coutinho et al 2005), ATM (Eng et al 2004;Coutinho et al 2005), and PMM2 (Schollen et al 2007), resulting in inherited growthhormone-insensitivity disease, Duchenne muscular dystrophy, ataxia telangiectasia, and congenital disorders of glycosylation type 1a and other genetic disorders (Harland et al 2001;King et al 2002).…”