A recurrent signal peptide mutation in the growth hormone releasing hormone receptor with defective translocation to the cell surface and isolated growth hormone deficiency.
BACKGROUND
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.


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.


CONCLUSIONS
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.
Godi
Michela
M
Laboratory of Human Genetics, Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont, 28100 Novara, Italy.
Mellone
Simona
S
Petri
Antonella
A
Arrigo
Teresa
T
Bardelli
Claudio
C
Corrado
Lucia
L
Bellone
Simonetta
S
Prodam
Flavia
F
Momigliano-Richiardi
Patricia
P
Bona
Gianni
G
Giordano
Mara
M
D000328:Adult; D015153:Blotting, Western; D001827:Body Height; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D002869:Chromosome Aberrations; D005260:Female; D005455:Fluorescent Antibody Technique; D005808:Genes, Recessive; D014644:Genetic Variation; D005838:Genotype; D005998:Glycine; D006579:Heterozygote; D019382:Human Growth Hormone / Q000172:deficiency*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010957:Plasmids; D012333:RNA, Messenger / Q000302:isolation & purification; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*; D014162:Transfection; D014633:Valine
D012333:RNA, Messenger; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D019382:Human Growth Hormone; C048250:somatotropin releasing hormone receptor; D014633:Valine; D005998:Glycine