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GROWTH, GENETICS & HORMONES
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insulin-like growth factor
(IGF)-I in the 2 families
may be related to the
well-known limitations
of the current methods
of clinical investigation.
This study, along with the
mutated murine models,
supports the (debated)
view that ghrelin and
GH/IGF-I interact in the
control of growth.
Inheritance of the A204E GHSR mutation in families 1 and 2. (A) Family 1. (B) Family 2. Circles and squares
denote female and male family members, respectively. The SD to mean height for age is given below each
symbol; height values are before GH treatment. Black symbols denote a short stature. The probands are
indicated by arrows. The segregation of the GHSR A204E allele within both families was carried out by
means of a specific restriction fragment length polymorphism (the A204E mutation creates an MnlI site).
Reprinted with permission: Pantel J, et al. J Clin Invest. 2006;116:760-768. Copyright © American Society
for Clinical Investigation. 2006. All rights reserved.
and both heterozygous. The 3 patients who received GH
treatment increased their growth velocity.
The mode of action of this mutation was carefully
analyzed showing that it was a significantly impaired
functional activity of the receptor:
• The A204E mutant was efficiently translated into
a protein, but with only a small fraction properly
expressed at the cell surface. This plasma membrane
fraction displayed a normal activity for ghrelin.
• The mutation led to a loss of constitutive activity of
the receptor, ie, ligand-independent activity. Some
experiments using an in vitro transcription system
also suggest the absence of negative dominant effect
of the mutant over the wild-type.
• Ghrelin was able to stimulate in vitro the c-AMP
response element (CRE) pathway through the
mutant receptor in spite of its decreased cell-surface
expression.
Pantel et al concluded that the involvement of
the GHSR A204E mutation in SS transmitted over 2
generations was supported by the following evidence: all
patients within the 2 families carried this mutation which in
turn was absent in an appropriate control population; the
mutation and the amino acid polarity predicts changes in
molecular activity; and the findings point to a functional
importance of the GHSR constitutional activity.
The authors speculated that given the documented
pharmacological effects of ghrelin on GH release, the
SS results from abnormal regulation of the GH axis.
The heterogeneity of the findings related to GH and
Pantel J, Legendre M, Cabrol
S, et al. Loss of constitutive
activity of the growth hormone
secretagogue receptor in
familial short stature. J Clin
Invest. 2006;116: 760−768.
Editor’s Comment: This
is an elegant and wellconducted
study that
introduces the concept
of fine regulation of
growth by a mutation of a
receptor which until now
did not prove to be essential in achieving normal stature.
In addition, it provides evidence for the in vivo importance
of its ligand independent signalling as expressed by its
constitutive activity. An interesting “commentary” paper
is published in the same issue by Holst and Schwartz 3 ;
they refer to a previous German case of ISS and the
same mutation 4 and also point out that obesity is an
additional symptom that segregates with this mutation and
a Phe279Leu mutation which shares the same effect on
receptor constitutive activity. Holst and Schwartz suggest
that selective loss of ghrelin receptor constitutive activity
causes a syndrome of SS and obesity developing around
puberty. How these molecular changes impair growth and
GH secretion and furthermore, how they are involved in
hunger control and obesity, remains in part speculative
and challenging for future research.
It is interesting that clinical and genetic investigation
essentially by systematic structure-function analysis opens
new physiological concepts. It should be taken into account
when performing population studies on the multifactorial
control of growth and, more specifically, by GH and IGF
secretion and activity. In addition, these studies open new
possible mechanisms on the weight-to-height relationship
in patients with SS. The authors briefly commented on the
positive response to GH therapy in 3 patients. Eventually,
their data, part of which are presented in the Table, would
deserve an additional publication. More studies need to be
performed in order to consider the potential development
of pharmacological tools in relation to this uncommon and
likely pathophysiology of SS and/or obesity.
Raphaël Rappaport, MD
28 GGH Vol. 22, No. 2 June 2006 www.GGHjournal.com
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