RAPID COMMUNICATIONS: Mutations in the Preproghrelin/Ghrelin Gene Associated with Obesity in Humans

Abstract

Ghrelin and preproghrelin sequences were determined in 96 unrelated female subjects with severe obesity (mean body mass index (BMI) 42.3 +/- 3.4 kg/m(2)) and in 96 non-obese female controls (mean BMI 23.0 +/- 1.4 (kg/m2) of the Swedish Obese Subjects cohort. A mutation at amino acid position 51 (Arg51Gln) of the preproghrelin sequence that corresponds to the last amino acid in mature ghrelin product was identified in six (all heterozygotes) obese subjects (6.3%) but not among controls (p < 0.05). The self-reported weight at 20, 30, and 40 years of age tended to be 7.5, 4.7 and 6.4 kg lower, respectively, among obese Gln allele carriers versus obese non-carriers. In addition, a mutation at codon 72 of the preproghrelin gene (Leu72Met) was detected in 15 obese (12 hetero- and 3 homozygotes) and 12 control (all heterozygotes) subjects. This mutation outside the coding region of the mature ghrelin product tended to be associated with lower age of self-reported onset of obesity (15.6 +/- 7.9 vs. 20.5 +/- 10.5 years; p = 0.09). In addition to these two mutations in coding regions, a G274A base change in a non-coding region between exons one and two was found only in two obese individuals. The Arg51Gln amino acid substitution may alter the cleavage site of endoproteases and the length of the mature ghrelin product. The functional significance of the Leu72Met mutation and a G274A base change remains to be determined. In conclusion, the data provide evidence that a low frequency sequence variation in the ghrelin gene could play a role in the etiology of obesity.

Ghrelin Arg51Gln mutation is a risk factor for Type 2 diabetes and hypertension in a random sample of middle-aged subjects

“…The Arg51Gln mutation disrupts the recognition site in the last codon of the mature ghrelin product [5]. Interestingly, the mutation was associated with lower IGF-I concentrations which, in most conditions, reflect the GH concentrations quite well [8].…”

“…The 618 bp DNA fragment covering the exons 1 and 2 that encompass the entire ghrelin product was amplified from leukocyte DNA using the PCR technique (forward primer: 5′-GCTGGGCTCCTACCTGAGC-3′, reverse primer: 5′-GGACCCTGTTCACTGCCAC-3′) [5]. The Arg51Gln mutation was identified using restriction endonuclease SacI, which retains the mutated site (guanine replaced by adenine) at base 346 in exon 2 of the preproghrelin gene undigested.…”

“…The Arg51Gln mutation changes the carboxyterminal amino acid of the mature hormone [5] and is associated with lower ghrelin concentrations [6]. We therefore assessed the hypothesis that the Arg51Gln mutation might be a risk factor for Type 2 diabetes, IGT, and hypertension.…”

Molecular genetics of human growth hormone, insulin-like growth factors and their pathways in common disease

“…Mutations in other genes aVecting synthesis, release or action of GH, with eVects on metabolic traits, have been described, including mutations in GHRHR (Wajnrajch et al 1996;Salvatori et al 2001), GHRL (Ukkola et al 2001a;Hinney et al 2002a) and SSTR5 (Ballare et al 2001).…”

Growth Hormone Secretagogues and Ghrelin: An Update on Physiology and Clinical Relevance

“…Recently, three mutations in the preproghrelin/ghrelin gene were identified which are associated with obesity [33]. Ghrelin and preproghrelin sequences were determined in 96 unrelated female subjects with severe obesity and in 96 non-obese female controls.…”