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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  )
- Rosenfeld RG, Hwa V. Toward a molecular basis for idiopathic short stature. J Clin Endocrinol Metab 2004;89:1066-1067.
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Current GGH - Vol. 24 No. 1
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