Is the Laron Mouse an Accurate Model of Laron Syndrome?

Abstract

The classical form of Laron syndrome (LS: growth ormone, GH, resistance or insensitivity) (1,2) is an xample of deletions or mutations in the GHR gene esulting in dysfunction of the GH receptor (R) (3). bout 25 different mutations (partial gene deletions, onsense and missense point mutations) have been escribed in various families (4–12). When, as is the ase in most patients, the mutation is located in the xtracellular domain of the GHR, affected patients lso have absent or very low growth hormone-bindng protein (GHBP) (13–17). Of interest in this context are two defects that esult in elevated GHBP and GH resistance denotng a defect in the GH signal transmission. The first s a splice-site mutation in exon 8 that abolishes the ransmembrane helix and severely truncates the inracellular domain (10). The other is an intronic oint mutation consisting of a G to T substitution in he splice acceptor site preceding exon 8 (18) that esults in altered GHR precursor mRNA splicing nd an inactive GHR. Another interesting mutation nvolves the carboxy-terminal part of the GHBP (a egion adjacent to the transmembrane domain of the HR) and prevents GHR dimer stabilization via irect GHR-GHR contact (7). In this mutant GHR/ HBP, GH binding is normal but the GHR fails to roperly dimerize and transduce a biological signal. utations in the intracellular domain of the GHR nclude two noncontiguous base substitutions in the ame patient (7), and a dominant negative mutation n the proline-rich region that results in the inability f the GHR to transduce intracellular signals (11). An undefined postreceptor defect has also resulted C i w