End Organ Targets and Receptors

The GH receptor (GHR) gene has been isolated in humans to the proximal short arm of chromosome 5 (5p13.1-12) (96). The translated product is a 620 amino acid protein encoded by nine exons (numbered, interestingly, 2-10) for the secretion signal (exon 2), extracellular domain (exons 3-7), transmembrane domain (exon 8), and intracellular domain (exons 9-10) (97). The extracellular domain is also found in circulating serum as GH binding protein. The GHR has homology with the prolactin receptor, and it belongs to the cytokine family ofreceptors that are associated with JAK2, a ligand-activated tyrosine kinase (98). JAK2 phosphorylates both the GHR and the cytoplasmic transcription factors known as STATs (99). After phosphorylation, STATs dimerize and move to the nucleus, where they activate gene transcription.

In most tissues where GH acts, it activates transcription of the IGFs (Fig. 1). The IGFs are a peptide family with diverse metabolic roles that include mediating many of the anabolic and mitogenic actions of GH. IGF-1 is a basic 70 amino acid peptide, while IGF-2 is a slightly acidic 67 amino acid peptide (100). Structurally similar to insulin, they are comprised of A and B chains connected by disulfide bonds (101).

The IGF-1 gene, located on the long arm of chromosome 12, spans 95 kb and contains at least six exons (102,103). Although GH appears to be the primary regulator of IGF-1 gene expression, transcriptional control is complex. It is influenced by nutritional status, GH, hCS, prolactin, glucocorticoids, sex steroids, thyroid hormones and insulin (104-107). The IGF-2 gene is 35 kb in length, contains nine exons, and is located adjacent to the insulin gene on the short arm of chromosome 11 (102,108).

The action of IGFs occurs through two IGF receptors and the insulin receptor. The type 1 IGF receptor gene appears to be the major somatogenic mediator. It is structurally closely related to the insulin receptor and binds both IGF-1 and IGF-2 with high affinity. It is located on the long arm of chromosome 15.

Unlike GH, the IGFs appear to play a major role in prenatal growth. Reece et al. and Verhaeghe et al. found a direct correlation between neonatal weight and cord serum IGF-1 levels (109,110). In 1996, Roth et al. confirmed that cord IGF-1 levels correlate with fetal size even in the macrosomia associated with diabetic pregnancies (111). It has been proposed that fetal IGF release is in part stimulated by growth hormone-like factors produced by the placenta in response to placental GHRH (111,112).

The IGFs in plasma are complexed to carrier proteins with molecular weights of 28-150 kDa. These high-affinity binding proteins (BPs) serve to extend the IGFs serum half-life, to convey IGFs to target cells, and to modulate the IGFs interaction with their receptors. Six distinct human IGFBPs have been cloned and sequenced (113,114); at least four IGFBP-related proteins have also been identified (reviewed in 115). IGFBP-3 transports over 90% of the circulating IGF in adult serum. In general, IGFBPs modulate the mitogenic and proliferative actions of IGF, apparently by competing with IGF receptors for IGF peptides and by transporting IGFs to target tissues (116).

Growth Hormone Receptor Defects

As noted above, most patients with Laron syndrome have been found to have GHR defects. This was first indirectly proven in 1984 by Eshet et al., who found that patients with Laron syndrome had a lack of GH binding activity in liver biopsies (117). In 1987, Baumann et al. found that these persons also did not have circulating serum GHBP (118). The first GHR mutation was found by Amselem et al. in 1989 (119). Since then, many other GHR mutations have been described (Table 4) (120-129).

Many of these GHR mutations affect the extracellular domain and therefore manifest with absent or decreased levels of GHBP. Godowski et al. found one such mutation in two patients of Iranian descent, who had deletions of exons 3, 5, and 6 (with retention of exon 4) (97). Berg et al. (1992) found a A^G substitution, which resulted in a new splice site and a truncated exon 6 (121). Another identified GHR mutation is a Phe96^Ser change from a T^C substitution in the extracellular domain (119). This Phe96is evolutionarily conserved in all members of this class of transmembrane receptors. A mutation in this amino acid does not diminish receptor binding, but interferes with intracellular trafficking (130).

Other identified GHR defects do not affect the extracellular domain region, and therefore manifest with normal or even elevated GHBP levels. Screening of children with idiopathic short stature for GHR defects is now underway (131). It has been hypothesized that GHR defects may prove to be a relatively common GHAD, accounting for up to 5% of all cases of idiopathic short stature (132).

Patients with GHI from GHR defects often do not respond well to exogenous GH therapy. Some patients have been treated with IGF-1 (133-135). In 1992, a 7-day trial of IGF-1 therapy in six adults with GHR defects revealed no adverse effects (136). A subsequent recent collaborative study examined IGF-1 therapy over 2 years in five patients with GHI and high basal GH levels and in three patients with complete GHD and growth hormone antibodies (133). The investigators found that with twice-daily subcutaneous IGF-1 treatment, these children initially had a greatly increased growth velocity (from 4.0 cm/yr pre-treatment to 9.3 cm/yr). After the first year, growth rate slowed (to 6.2 cm/yr), but was still significantly greater than pre-IGF-1 treatment. Some patients on high dose (120 ^g IGF-1/kg twice daily) treatment developed hypoglycemia; others had selective acceleration of lymphoid and renal tissue growth. It remains to be seen if IGF-1 will cause sustained gain of height velocity without significant attenuation or undesirable side effects.

IGF-Related Defects

Children with primary IGF-1 deficiency have the same phenotype as those with GH gene deletions. A boy with severe prenatal and postnatal growth failure has been described with a homozygous partial IGF-1 gene deletion (137). His growth failure was associated with bilateral sensorineural deafness, delayed motor development, and behavioral difficulties (hyperactivity and short attention span). He did not have a significant delay in bone age or hypoglycemia. An IGFBP-3 level was normal. This case suggests that IGF-1 has a role not only in GH action, but also in CNS development and function.

It is likely that GHAD also can result from post-GHR signal transduction defects (for example JAK2 defects) or from defects in the IGF-1 receptor. Such mutations could produce GH insensitivity with normal to high levels of IGFs or IGFBPs. These have been

Table 4 Described GHR Mutations

Domain Ref.

Extracellular domain

Cys38^Stop (homozygous) (120)

Arg43^Stop (homozygous) (120)

Glu44^Lys (compound heterozygote) (124)

46 del TT (homozygous, compound heterozygote) (123)

71+1 G^A (compound) heterozygote) (123)

Phe96^Ser (homozygous) (119)

Cys122^Stop (heterozygous) (124)

Prom^Gln (homozygote) (129)

Arg161^Cys (compound heterozygote) (124)

Codon 180 A^G (homozygous)3 (121)

Arg211^His (heterozygous) (124)

Arg217^Stop (heterozygous?) (123)

Glu224^Asp (heterozygous) (124)

Glu224^Stop (compound heterozygote) (127)

230 del TA or AT (homozygous) (123)

Complex gene deletion of exons 3,5,6 (97) Transmembrane domain

Exon 8 splice donor site G^Ca (homozygous) (125) Intracellular domain

Codon 310 C deletion/frameshift (compound heterozygote) (127)

Cys422^Phe (heterozygous) (122)

Pro561^Thr (heterozygous) (122)

Exon 9 splice acceptor cite G^C (homozygous) (126)

Intron 9 splice donor site (128)

aDoes not change encoded amino acid, but changes splice site.

searched for but are yet to be described; it appears that IGF-related mutations will be an infrequent cause of clinical GH deficiency (138). It is possible that mutations that inactivate IGF-1 are lethal.

Some cases of growth failure, however, have been attributed to IGF-1 resistance (139-141). Bierich et al. described a child who was 3 kg and 48 cm at birth, and by the age of 3 had a height 8 standard deviations below the mean (140). Laboratory analysis showed that she had elevated GH levels with elevated IGF-1 levels. Cultured skin fibroblasts had a 50% reduction in IGF-1 binding capacity. Subsequent study by Heath-Monnig et al. in a similar patient showed that the ability of IGF-1 to stimulate fibroblast a-aminoisobutyric acid uptake was markedly diminished compared to control subjects (141). The reported patients have had birth lengths less than the fifth percentile (48, 47.5, and 45 cm), again emphasizing the importance of IGF-1 in fetal growth.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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