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 micrograms/l), low IGF-I (2.7 nmol/l) and IGFBP-3 (410 micrograms/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 the GHBP was approximately 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 micrograms/l vs 0.76 +/- 0.13 microgram/l, p < 0.001). Serum IGF-I and IGFBP-3 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 micrograms/l). All the subjects' heights were within the normal range. Analysis of the GHR gene performed in the proband revealed an as yet undescribed homozygous 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.

[1]  S. Amselem,et al.  Alternatively spliced forms in the cytoplasmic domain of the human growth hormone (GH) receptor regulate its ability to generate a soluble GH-binding protein. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Amselem,et al.  Molecular basis of inherited growth hormone resistance in childhood. , 1996, Bailliere's clinical endocrinology and metabolism.

[3]  A. Clark,et al.  A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein. , 1996, The Journal of clinical endocrinology and metabolism.

[4]  G. Baumann,et al.  The stoichiometry of growth hormone-binding protein complexes in human plasma: comparison with cell surface receptors. , 1994, The Journal of clinical endocrinology and metabolism.

[5]  A. Karasik,et al.  Laron syndrome due to a post-receptor defect: response to IGF-I treatment. , 1993, Israel journal of medical sciences.

[6]  S. Amselem,et al.  SPECTRUM OF GROWTH HORMONE RECEPTOR MUTATIONS AND ASSOCIATED HAPLOTYPES IN LARON SYNDROME , 1993, Pediatric Research.

[7]  Y. Le Bouc,et al.  Familial short stature with very high levels of growth hormone binding protein. , 1993, The Journal of clinical endocrinology and metabolism.

[8]  A. Karasik,et al.  Long-term treatment of Laron type dwarfs with insulin-like growth factor-1 increases serum insulin-like growth factor-binding protein-3 in the absence of growth hormone activity. , 1993, Acta endocrinologica.

[9]  M. Ranke,et al.  Classification of growth hormone insensitivity syndrome. , 1993, The Journal of pediatrics.

[10]  I. Robinson,et al.  Growth hormone (GH) binding protein and GH interactions in vivo in the guinea pig. , 1992, Endocrinology.

[11]  M. Shaw,et al.  A second, lower affinity growth hormone-binding protein in human plasma. , 1990, The Journal of clinical endocrinology and metabolism.

[12]  L. Meacham,et al.  Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Z. Laron,et al.  Serum GH binding protein activities identifies the heterozygous carriers for Laron type dwarfism. , 1989, Acta endocrinologica.

[14]  Z. Laron,et al.  SERUM GROWTH HORMONE BINDING PROTEIN ACTIVITY IN HEALTHY NEONATES, CHILDREN AND YOUNG ADULTS: CORRELATION WITH AGE, HEIGHT AND WEIGHT , 1989, Clinical endocrinology.

[15]  T. Buchanan,et al.  In vivo kinetics of a covalent growth hormone-binding protein complex. , 1989, Metabolism: clinical and experimental.

[16]  H A Erlich,et al.  Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[17]  William I. Wood,et al.  Growth hormone receptor and serum binding protein: purification, cloning and expression , 1987, Nature.

[18]  M. Shaw,et al.  Absence of the plasma growth hormone-binding protein in Laron-type dwarfism. , 1987, The Journal of clinical endocrinology and metabolism.

[19]  Marvin B. Shapiro,et al.  RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. , 1987, Nucleic acids research.

[20]  W. Daughaday,et al.  Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism). , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A C Herington,et al.  Identification and characterization of specific binding proteins for growth hormone in normal human sera. , 1986, The Journal of clinical investigation.

[22]  M. Binoux,et al.  Analysis of serum insulin-like growth factor binding proteins using western blotting: use of the method for titration of the binding proteins and competitive binding studies. , 1986, Analytical biochemistry.