MOLECULAR ANALYSIS OF TWO FAMILIES WITH LARON SYNDROME AND POSITIVE GROWTH HORMONE BINDING PROTEIN

Abstract

Using linkage analysis, we previously showed that the growth hormone receptor (GHR) was involved in Laron dwarfism, an autosomal recessive GH resistant disorder. Interestingly, the extracellular domain of the GHR is found in the serum in the form of a hormone binding protein (GHBP), which binds GH with approximately the same affinity as the native receptor and which is undetectable, in terms of binding activity, in the serum of patients with Laron syndrome. We have analyzed the GHR gene in two unrelated Asian families in which patients displayed the classical features of Laron phenotype except for the presence of serum GH binding activity. To evaluate the involvement of the GHR in ihis new phenotype, we first performed linkage studies: in one family, the GHR markers cosegregated with the disease phenotype whereas the other family was not informative. Analysis of the coding region of the GHR gene revealed, in both families, a missense defect (Asp152→His) within the exoplasmic domain of the receptor. Expression of Ihe corresponding mutated cDNA into eukaryotic cells led to the synthesis of a receptor that displayed normal binding kinetics. We expect that this mutation is deleterious since it is linked to the disease phenotype and involves a highly conserved amino acid. In addition, previous studies have shown that the complex between GH and the extracellular domain of its receptor (GHBP) consists of one molecule of GH per two molecules of GHBP (1 and II) and that hormone-induced receptor dimerization is relevant to the signal transduction mechanism. Interestingly, since the mutation described is located at the GHBPI / GHBPII interface, it is very probable that it plays a critical role in growth signal transduction.