A HOMOZYGOUS SPLICE-SITE MUTATION AFFECTING THE INTRACELLULAR DOMAIN OF THE GROWTH-HORMONE (GH) RECEPTOR RESULTING IN LARON SYNDROME WITH ELEVATED GH-BINDING PROTEIN

Laron syndrome (LS) is a severe autosomal recessive form of GH resista nce resulting from molecular defects in the GH receptor (GHR). Affecte d individuals have extreme short stature and a typical facial phenotyp e. The point mutations in the GHR gene identified in this condition ha ve until now been confined to the region encoding the extracellular do main of the receptor. We report here the first homozygous point mutati on within the intracellular domain of the GHR in two LS cousins distin guishable from classical LS patients only by the presence of elevated GH-binding protein (GHBP) in their serum. A G to C transversion at the vital -1 position in the splice donor site of exon 8 disrupts normal splicing, resulting in the complete skipping of exon 8, producing a mu tant GHR protein lacking transmembrane and intracellular domains. We p redict that this mutant protein would not be anchored in the cell memb rane and would be measurable in the circulation as GHBP, hence explain ing the phenotype of severe GH resistance combined with elevated circu lating GHBP.