Abstract
Growth hormone inscnsitivity syndrome (GHIS or Laron syndrome) is an autosomal recessive disorder caused by mutations in the gene for the growth hormone receptor (GHR). This gene, located on chromosome region 5p13.1-p12 (1) encodes a 620 amino acid protein with a centrally located hydrophobic transmembrane domain. Proteolylic cleavage of the extracellular domain that includes the growth hormone binding site generates the circulating GHBP. One OH molecule binds to two GHBP molecules resulting in dimerization of the receptors, possibly an essential step for signal transduction.
In order to detect GHR mutations in patients with GHIS, a screening procedure has been devised (2,3). All nine cxons and surrounding splice junctions of the GHR gene are amplified by PCR with primers designed from the published sequence. Each PCR product is analysed for altered melting behavior by denaturing gradient gel electrophoresis (DGGE). A GC-clamp is added to one primer to ensure complete analysis of the entire exon and splice site regions. PCR products that are positive by DGGE screening are sequenced either directly or after subcloning. In our laboratory, Dr. Mary Anne Berg has identified two nonsense mutations (R43X and R217X), two splice junction mutations (189-1 G-to-T and 71 + 1 G-to-A) and two frameshift mutations leading to translational stop codons (46 del TT and 230 del TA) all of which involve either exon 4 or exon 7 (3). The most unusual mutation - that she has detected in over 50 affected individuals from Ecuador - involves a single nucleotide substitution in codon 180 that does not change the amino acid encoded (E180E). The A-to-G transversion, however, creates a new 5′ splice site which is exclusively used and leads to an in-frame deletion of 24 nucleotides from exon 6 in the patients' mRNA (2). Since the GH binding and receptor dimeriration sites would remain intact but no response to GH has been reported in these patients, the mutant receptor protein is postulated to undergo abnormal folding and intracellular degradation. The E180splice mutation has not been detected in any patients outside of Ecuador.
In general, the mutations are unique to particular families or geographic areas. Only R43X has recurred on different haplotype backgrounds. All mutations we have identified so far are predicted to result in complete absence of a functional receptor protein. Thus, it is not surprising that affected individuals who are homozygoles for particular mutations or compound heterozygotes for two different mutations are clinically indistinguishable. The variable GHBP levels, by indirect immunochemistry, that have been reported among individuals homozygous for the same mutation, remain unexplained. Curiously, all reported mutations involve the extracellular domain. The intracellular domain encoded by one small and one very large exon may present a less favorable target for mutations, or such mutations could cause a different phenotype.
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Francke, U. GROWTH HORMONE INSENSITIVITY SYNDROME. Pediatr Res 33 (Suppl 5), S7 (1993). https://doi.org/10.1203/00006450-199305001-00027
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DOI: https://doi.org/10.1203/00006450-199305001-00027