Dysfunctional Growth Hormone Variant

In order to expand the known mutational spectrum of the growth hormone (GH) gene, 74 patients with familial short stature were screened for mutations in the pituitary-expressed GH1 gene. Two novel mutations were identified: a missense mutation Ile179Met substitution and a — 360AÆG promoter variant; and two other previously known heterozygous lesions were also detected: a Val110Ile variant polymorphism and a Thr-24Ala neutral polymorphism. The Ile179Met variant exhibited a similar degree of resistance to proteolysis and secretion as the wild type GH. Molecular binding studies suggested that the Ile179Met substitution perturbed the interactions between the GH and the GH receptor affecting signaling transduction. This resulted in 50% reduced extracellular related kinase (ERK) activation as compared with that induced by the wild type GH. The authors concluded that these mutations reduced the ERK pathways activation and may thus play a role in mediating GH action of patients with familial short stature (SS).

Lewis MD, Horan M, Millar DS, Newsway V, Easter TE, Fryklund L, Gregory JW, Norin M, Del Valle CJ, Lopez-Siguero JP, Canete R, Lopez-Canti LF, Diaz-Torrado N, Espino R, Ulied A, Scanlon MF, Procter AM, Cooper DN. A novel dysfunctional growth hormone variant (Ile179Met) exhibits a decreased ability to activate the extracellular signal-regulated kinase pathway. J Clin Endocrinol Metab 2004;89:1068-1075.

Editor’s Comment: This paper provides the molecular evidence that accounts for the growth failure of some patients with familial SS. It further expands the knowledge of the growth alterations in the presence of normal GH secretion, defined as peak GH levels higher than 10ng/ml after provocative stimulation. There may be other alterations of the GH secretion and/or signaling pathway that lead to SS without altering circulating GH levels. These can be detected in as many as 25% of children with idiopathic SS if appropriately investigated with sophisticated techniques not readily available to the clinician.

The accompanying editorial succinctly reviewed the known molecular alterations associated with SS.¹ If we look we will continue to find other mechanisms accounting for growth alterations and/or SS. The etiology of some SS patients with short parents has been clearly elucidated by these investigators.

Fima Lifshitz, MD

References - (linked to )

1. Rosenfeld RG, Hwa V. Toward a molecular basis for idiopathic short stature. J Clin Endocrinol Metab 2004;89:1066-1067.