GHRH Receptor Mutation Research Articles

Three new mutations in the gene for the growth hormone (gh)-releasing hormone receptor in familial isolated gh deficiency type ib.

Isolated GH deficiency (IGHD) is familial in 5-30% of cases. The majority of patients have the type IB form, characterized by autosomal recessive transmission, low but measurable serum concentrations of GH, and responsiveness to exogenous GH therapy. Unique mutations in the gene encoding the GHRH receptor (GHRHR) have previously been described in 2 kindreds with IGHD IB. However, the prevalence of GHRHR mutations in patients with IGHD IB is unknown. We analyzed 30 families with IGHD IB in which more than 1 member was affected. Linkage analysis was performed in 28 of the families, and in 3 families sibling pair analysis indicated linkage to the GHRHR gene locus. These 3 families as well as 2 families in which linkage analysis was not performed were screened for mutations in the 13 coding exons, the intron-exon boundaries, and 327 bases of the promoter of the GHRHR gene. We identified novel GHRHR missense mutations in 2 of the 3 kindreds with informative linkage and in 1 family in which linkage had not been performed. In 1 family affected members were homozygous for a mutation in codon 144 that replaces leucine with histidine (L144H). Affected subjects in a second family were compound heterozygotes, carrying both the L144H mutation and a second mutation in codon 242 that replaces phenylalanine with cysteine. Affected subjects in a third family were homozygous for a mutation that replaces alanine at codon 222 with glutamic acid. All 3 mutations segregated with the IGHD phenotype. All 3 mutant receptors were expressed in CHO cells, and each failed to show a cAMP response after treatment of the cells with GHRH. These results demonstrate that missense mutations in the GHRHR gene are a cause of IGHD IB, and that defects in the GHRHR gene may be a more common cause of GH deficiency than previously suspected.

Familial Isolated Growth Hormone Deficiency Is Associated with Hypertension, Central Obesity and Dyslipidemia But not the Classical Syndrome X

69 We have described a splice mutation in the GHRH receptor gene (G to A at position +1 , intron 1) in Itabaianinha county, Sergipe, Brazil. These genetically homogeneous individuals provide a unique opportunity to investigate the effects of isolated growth hormone deficiency [GHD] on cardiovascular risks. Therefore, we studied 16 dwarfs with GHD and no past of growth hormone therapy (8M:8F,49±14 yrs) and 31 age-matched normal controls [C] (12M:19F,44±12 yrs). We have examined insulin-like growth factor 1(IGF-1), arterial blood pressure, body mass index (BMI), waist-to-hip ratio (WHR), body composition by near infra-red interactance,leptin,serum lipids, uric acid, fasting glucose and insulin. IGF-1 in GHD was markedly lower (2.7±1.8 vs 154.9±82 ng/mL; p<0.001). Systolic blood pressure was higher in GHD (147±37 vs 129±24 mmHg; p=0.046) but diastolic blood pressure was similar (84±16 vs 80±16 mmHg; p=NS). BMI (22.9±4.1 vs 24.4±3.8 Kg/m 2 ;p=NS) and leptin (11±8.9 vs 10.2±11.3 ng/mL;p=NS) were similar (GHD vs C), but WHR (0.97±0.08 vs 0.90±0.08; p=0.01) and % of fat mass (34±7 vs 21±10 %;p<0.001)were higher in GHD. Total cholesterol (236±53 vs 195±38 mg/dL;P=0.003) and LDL-C (165 ±47 vs 133±32 mg/dL;p=0.009) were higher in GHD but no differences were observed in HDL-C (40±9 vs 38±7 mg/dL;p=NS), apo B (1.16±0.36 vs 1.33±0.96 g/L; p=NS) and triglycerides (158±117 vs 115±62 mg/dL;p=NS). Uric acid was higher in GHD (4.0±1.2 vs 3.3±0.8; p=0.02). Despite central obesity and hypertension, fasting glucose (86±11 vs 87±14 mg/dL;p=NS),fasting insulin (2.9±2.4 vs 4.3±3.4 μU/mL;p=NS) and insulin/glucose ratio (0.03±0.03 vs 0.05±0.03μU/mL;p=NS) were smaller but not significantly in GHD. We conclude that GHD due to this GHRH receptor mutation is associated with systolic hypertension, central obesity and dyslipidemia with some features different from the classical syndrome X. These data suggest that in GHD another mechanism different from insulin resistance participate in the pathogenesis of hypertension and metabolic alterations.

Familial growth hormone deficiency with mutated GHRH receptor gene: clinical and hormonal findings in homozygous and heterozygous individuals from Itabaianinha.

To characterize clinically and hormonally the syndrome of autosomal recessive familial growth hormone deficiency (FGHD) recently identified in Itabaianinha, Sergipe, Brazil, caused by a novel mutation (mt) that inactivates the growth hormone-releasing hormone receptor (GHRH-R) gene. Clinical and hormonal evaluations were performed in 21 FGHD individuals (mt/mt group) aged 8 to 63 years, 13 heterozygotes for the GHRH-R mutation (wt/mt group) and 5 homozygotes for the wild type (wt) allele (wt/wt group), identified by genotyping of peripheral blood leukocyte DNA. Clinical and hormonal characterization included physical examination and measurement of GH, IGF-I, IGF binding protein-3 (IGFBP-3), cortisol, prolactin, LH, FSH, and free thyroxine (FT4). Clinical features were consistent with isolated growth hormone deficiency. Height was significantly reduced in the mt/mt group compared with the wt/mt group (mean height standard deviation score (SDS) +/- s.d.: -7.35+/-1.37 vs -1.84+/-1.44 respectively, P<0. 0001), and the wt/wt group (-1.85 +/- 0.81, P=0.0007). The height of the 13 wt/mt subjects did not differ from the 5wt/wt individuals. Serum GH, IGF-I, IGF-I SDS, IGFBP-3 and IGFBP-3 SDS were all significantly lower in the mt/mt group than in the wt/mt and wt/wt groups. Two affected children treated with GH for 1 year showed a normal growth response. Serum IGF-I and IGF-I SDS were lower in wt/mt compared with wt/wt group, but did not reach statistical significance. IGF-I and IGF-I SDS correlated inversely with age in wt/mt group. FGHD due to an autosomal recessive GHRH-R gene mutation leads to marked dwarfism, phenotypically and hormonally indistinguishable from other forms of isolated GH deficiency. Heterozygotes for the GHRH-R mutation appear to have a partial defect in the GH/IGF axis, with no apparent height impairment.

Effect of severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on insulin-like growth factors (IGFs), IGF-binding proteins, and ternary complex formation throughout life.

Measurement of the insulin-like growth factors (IGFs) and their binding proteins has become commonplace in the indirect assessment of the integrity of the GH axis. However, the relative effect of GH deficiency (GHD) on each component of the IGF axis and the merit of any one parameter as a diagnostic test have not been defined in a homogeneous population across all ages. We therefore measured IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, IGFBP-3, and acid labile subunit (ALS) in 27 GHD subjects (aged 5-82 yr) from an extended kindred in Northeast Brazil with an identical GHRH receptor mutation and in 55 indigenous controls (aged 5-80 yr). The effect of GHD on the theoretical distribution of IGFs between the IGFBPs and the ternary complex was also examined. All components of the IGF axis, measured and theoretical, showed complete separation between GHD and control subjects, except IGFBP-1 and IGFBP-2 concentrations, which did not differ. The most profound effects of GHD were on total IGF-I, IGF-I in the ternary complex, and ALS. The proportion of IGF-I associated with IGFBP-3 remained constant throughout life, but was significantly lower in GHD due to an increase in IGF-I/IGFBP-2 complexes. IGF-I in the ternary complex was determined principally by concentrations of ALS in GHD and IGFBP-3 in controls, implying that ALS has greater GH dependency. In the controls, IGF-II was associated primarily with IGFBP-3 and to a lesser extent with IGFBP-2, whereas in GHD the reverse was found. There was also a dramatic decline in the proportion of free ALS in GHD adults that was not evident in controls. As diagnostic tests, IGF-I in the ternary complex and total IGF-I provided the greatest separation between GHD and controls in childhood. Similarly, in older adults the best separation was achieved with IGF-I in the ternary complex, with free ALS being optimal in younger adults. Severe GHD not only reduces the amounts of IGFs, IGFBP-3, and ALS, but also modifies the distribution of the IGFs bound to each IGFBP. Diagnostic tests used in the investigation of GHD should be tailored to the age of the individual. In particular, measurement of IGF-I in the ternary complex may prove useful in the diagnosis of GHD in children and older adults, whereas free ALS may be more relevant to younger adults.