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
A. Silbergeld et al., 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, Journal of pediatric endocrinology & metabolism, 10(3), 1997, pp. 265-274
Laron syndrome (LS) is a hereditary form of GH resistance due to molec
ular defects in the GH receptor (GHR). Most of the identified mutation
s are located in the-extracellular domain of the receptor, resulting i
n a lack of serum GHBP in the majority of LS patients. We present an L
S 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 sh
ort stature (height SDS -5.1), high GH (250 mu g/l), low IGF-I (2.7 nm
ol/l) and IGFBP-3 (410 mu g/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 = 1.9 x 10(9) M-1 comparable to
that of normal sera (Ka = 1.7 - 2.1 x 10(9) M-1). The apparent MW of t
he GHBP was similar to 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 nor
mal adults (0.81 +/- 0.06 RSB) (p much less than 0.001). The remaining
subjects had normal or moderately elevated GHBP levels. Serum GH in a
dults with high GHBP was significantly elevated above control values (
6.0 +/- 0.9 mu g/l vs 0.76 +/- 0.13 mu g/l, p < 0.001). Serum IGF-I an
d IGFBP-3 levels were normal in all the subjects, with the exception o
f an aunt (IGF-I 3.9 nmol/l) and the proband's sister (IGFBP-3 460 mu
g/l) All the subjects' heights were within the normal range. Analysis
of the GHR gene performed in the proband revealed an as yet undescribe
d homozygous intronic point mutation. It consists of a G --> T substit
ution at nucleotide 785-1 preceding exon 8, a sequence that encodes th
e transmembrane domain. This mutation, which destroys the invariant di
nucleotide of the splice acceptor site, is expected to alter GHR mRNA
splicing and to be responsible for skipping exon 8. The resulting trun
cated protein that retains GH binding activity is probably no longer a
nchored in the cell membrane, affecting signal transmission in the hom
ozygous patient and causing high GHBP levels in the heterozygous relat
ives.