Heterozygosity for a Mutation in the Growth Hormone-Releasing Hormone Receptor Gene Does Not Influence Adult Stature, But Affects Body Composition

Abstract

Context: Biallelic mutations in the GHRH receptor (GHRHR) gene (GHRHR) are a frequent cause of isolated GH deficiency (IGHD).Although heterozygous carriers of these mutations appear normal, we hypothesized that heterozygosity for a GHRHR mutation might be associated with a subclinical phenotype. Methods:We studied members of a large Brazilian kindred with IGHD (Itabaianinha cohort) caused by a homozygous null GHRHR mutation. We compared 76 adult subjects (age, 25-75 yr) heterozygous for the mutation (WT/MT) with 77 sex-matched controls from the same population who are homozygous for the wild-type GHRHR allele (WT/WT). Results:We found no difference in adult height and SD score for serum IGF-I between the two groups. Body weight, body mass index, skin folds, waist and hip circumferences, and lean mass were all reduced in WT/MT subjects. Percentage fat mass and waist/hip ratio were similar in the two groups. Fasting insulin and homeostasis model assessment of insulin resistance were lower in WT/MT. The other biochemical parameters [total and fractionated cholesterol, triglycerides, lipoprotein (a), and C-reactive protein] were not different between the two groups.Conclusions: Heterozygosity for a null GHRHR mutation is not associated with reduction in adult stature or in serum IGF-I but is associated with changes in body composition and possibly an increase in insulin sensitivity. These effects do not seem to be modulated by changes in circulating IGF-I.

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation

“…Different from the homozygous affected young adults, who exhibit severe short stature, with decreased FFM (kg) and increased percent of FM (45), young adult subjects HTZ for the Itabaianinha GHRHR mutation show no significant difference in height, but have lower FFM, no difference in the percent of FM and a trend of reduction in FM, when compared with homozygous normal controls from the same kindred (78). We hypothesized that a partial reduction in GH secretion might cause these changes in body composition, without affecting height.…”

“…These features have been published in 42 different publications (2,19,22,25,27,29,30,31,32,33,36,37,38,40,41,44,45,46,47,48,49,50,51,52,53,54,56,57,61,62,63,64,66,67,68,74,75,76,77,78,79,80). We have used this experiment of nature to discover 'usual laws of nature' as suggested by William Harvey, and to understand some aspects of more common conditions such as short stature, insulin resistance, diabetes, atherosclerosis, osteoporosis, cancer and ultimately longevity.…”

Genes and networks expressed in perioperative omental adipose tissue are correlated with weight loss from Roux-en-Y gastric bypass

“…A genetic association study has shown that heterozygosity for a GHRHR mutation is associated with changes in body composition and possibly an increase in insulin sensitivity. 22 Glutamate dehydrogenase 1 is involved in glutamate catabolism. The activated glutamate dehydrogenase enhances oxidation of glutamate and, in turn, increases the regulation of insulin secretion.…”

Older individuals heterozygous for a growth hormone-releasing hormone receptor gene mutation are shorter than normal subjects

“…20 The possibility of a milder phenotype in heterozygous carriers of a GHRHR mutation has only been suggested recently. 15 In that early work we had not detected an effect on adult stature. That population was, however, composed mostly by young adults.…”

“…14 In a previous study of the Itabaianinha kindred, we have shown that adult MUT/N subjects have reduced weight, body mass index (BMI) and MM when compared with homozygous normal (N/N) subjects, but their adult stature is not significantly reduced. 15 However, only 10% of those individuals were ⩾ 60 years of age. We hypothesized that the height reduction may manifest itself during senescence.…”