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A Recurrent Signal Peptide Mutation in the Growth Hormone Releasing Hormone Receptor with Defective Translocation to the Cell Surface and Isolated Growth Hormone Deficiency

Laboratory of Human Genetics, Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (M.Go., S.M., L.C., P.M.-R., M.Gi.), and Unit of Pediatrics, Department of Medical Sciences (A.P., S.B., F.P., G.B.), University of Eastern Piedmont, 28100 Novara, Italy; Department of Pediatrics (T.A.), University of Messina, 98100 Messina, Italy; and Laboratory of Pharmacology (C.B.), Department of Medical Sciences, University of Eastern Piedmont, 28100 Novara, Italy

Address all correspondence and requests for reprints to: Mara Giordano, Department of Medical Sciences, University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy. E-mail: mara.giordano{at}med.unipmn.it.

Context: Mutations in the GHRH receptor (GHRHR) have been detected in the familial type-IB isolated GH deficiency (IGHD-IB) inherited as an autosomal recessive disorder and characterized by a low but detectable serum GH level and good response to substitutive GH therapy.

Objective: The aim of our study was the identification of mutations in sporadic patients with a IGHD-IB phenotype.

Subjects and Methods: The GHRHR gene was systematically screened by DHPLC in 134 IGHD patients with no family history of the disorder or declared parental consanguinity.

Results: We identified a novel variation, Val10Gly, within the signal peptide at the heterozygous state in three patients and in one of 1084 controls (P = 0.004), suggesting that it might contribute to IGHD. The functional analysis showed that the signal peptide is not cleaved from the mutant GHRHR, which in turn is not translocated to the cellular surface, demonstrating that 10Gly drastically affects the receptor correct processing. Because 10Gly was also present in normal-stature relatives of the patients as well as in a control, it is likely that it exerts its effects in the context of other genetic and environmental susceptibility factors.

Conclusion: At difference from previous papers reporting GHRHR mutations in familial cases with a clear recessive mode of inheritance, our study was conducted on a large sample of sporadic patients and allowed to discover a novel mechanism of the disease caused by a recurrent dominant mutation in the GHRHR signal peptide associated with incomplete penetrance.