Intronic mutation in the growth hormone (GH) receptor gene from a girl with Laron syndrome and extremely high serum GH binding protein: Extended phenotypic study in a very large pedigree

Laron syndrome (LS) is a hereditary form of GH resistance due to molecular defects in the GH receptor (GHR). Most of the identified mutations are located in the extracellular domain of the receptor, resulting in a lack of serum GHBP in the majority of LS patients. We present an LS patient with supranormal levels of serum GHBP, in addition to 35 of her-relatives. The proband is a 3.5 year-old Druse girl with severe short stature (height SDS -5.1), high GH (250 μg/l), low IGF-I (2.7 nmol/l) and IGFBP-3 (410 μg/l), both unresponsive to exogenous GH. The binding capacity of the serum GHBP was 22 nM (adult reference serum, 0.7 nM), with an affinity constant Ka = 1.9x10⁹ M^-1 comparable to that of normal sera (Ka = 1.7-2.1x10⁹ M^-1). The apparent MW of the GHBP was ~60-80 kDa, similar to that of control sera. In the proband's sister, parents, grandparents and uncles, extremely high GHBP values were observed (43.0 ± 4.8 RSB, n=10) compared with normal adults (0.81 ± 0.06 RSB) p<<0.001). The remaining subjects had normal or moderately elevated GHBP levels. Serum GH in adults with high GHBP was significantly elevated above control values (6.0 ± 0.9 μg/l vs 0.76 ± 0.13 μg/l, p<0.001). Serum IGF-I and IGFBP3 levels were normal in all the subjects, with the exception of an aunt (IGF-I 3.9 nmol/l) and the proband's sister (IGFBP-3 460 μg/l). All the subjects' heights were within the normal range. Analysis of the GHR gene performed in the proband revealed an as yet undescribed homezygous intronic point mutation. It consists of a G→T substitution at nucleotide 785-1 preceding exon 8, a sequence that encodes the transmembrane domain. This mutation, which destroys the invariant dinucleotide of the splice acceptor site, is expected to alter GHR mRNA splicing and to be responsible for skipping exon 8. The resulting truncated protein that retains GH binding activity is probably no longer anchored in the cell membrane, affecting signal transmission in the homozygous patient and causing-high GHBP levels in the heterozygous relatives.