Exon 5


Arg183His; altered secretory granules

Isolated growth hormone defeciency IA is usually caused by deletions of the GH1 gene. At a molecular level, these DNA deletions are usually 6.7, 7.0, or 7.6 kb in length, with approx 75% being 6.7 kb (13,14). Several additional cases with 45 kb deletions have also been reported in unrelated families from Turkey, Italy, and Asia (see Table 1) (14). DNA sequence analysis of the fusion fragments associated with the recurring 6.7 to 7.6 kb deletions has shown that they arose from homologous recombination between repeated sequences that flank the GH1 gene (15). Multiple studies indicate that about 15% of individuals with severe IGHD (-4.5 SD in height or lower) have GH1 gene deletions. In 10 GH gene deletion subjects identified in studies of 78 subjects with severe IGHD, 3 out of 10 (30%) developed anti-GH antibodies following treatment with rhGH (16).

Sequencing studies have detected point mutations causing IGHD-IA (17-19). In a consanguineous Turkish family, a G>A transition in the 20th codon of the GH1 signal peptide was found that converts a TGG (Trp) to a TAG (Ter) codon. In another patient, Duquesnoy et al. found a deletion that was inherited from one parent and a frameshift in the signal peptide of the GH1 gene that was inherited from the other (Table 1) (17). Because frameshift and nonsense mutations, as well as gene deletions, have been found to cause the IGHD IA pheno-type, this disorder is best described as complete GHD because of heterogeneous GH1 gene defects, rather than gene deletions alone (Table 1) (13,14).

A second autosomal recessive type of IGHD (IGHD IB) is characterized by the production of deficient but detectable amounts of GH after provocative stimuli. This contrasts with the absence of GH secretion that occurs in IGHD IA. In contrast to IGHD IA subjects, those with IGHD IB have no detectable GH1 gene deletions (20). The clinical criteria used to classify the IGHD IB phenotype include an accelerated growth response to rhGH (20). This observation and lack of anti-GH antibodies in those studied suggests that sufficient endogenous GH secretion occurs to prevent the anti-GH antibody production that characterizes IGHD IA. Interestingly, some subjects with IGHD IB have been shown to have intact secretory granules in their somatotropes and to exhibit normal GH responses to GHRH infusions (21,22). These observations suggest that the GH1 allele(s) are capable of some expression and that defects in GHRH or GHRHR synthesis or secretion might underlie this disorder. Using DNA sequence analysis of polymerase chain reaction (PCR) amplification products, Cogan et al. detected a point mutation causing IGHD IB (19). In a Saudi Arabian family, a G>C transversion was found that alters the first base of the 5' splice site (5'SS) of intron 4 (IVS4). This and other substitutions of the 5'SS perturb GH1 mRNA splicing and cause IGHD IB (Table 1). Abdul-Latif et al. identified a G>C transversion of the fifth base of the 5' SS of IVS4 in a consanguineous family with IGHD IB (Table 1) (23). Reverse transcription (RT)-PCR transcripts from lym-phoblasts of an affected patient demonstrated that the IVS4 +5G>C had the same effect on splicing as the IVS4 +1G>C. A fourth IGHD IB patient with severe growth retardation was found to have two different GH gene defects by Igarashi et al. One allele had a 6.7-kb GH gene deletion and the other had a 2-bp deletion in exon 3 (Table 1) (24). The 2-bp deletion causes a frameshift within exon 3, generating a premature stop codon within exon 4. The patient responded well to rhGH replacement therapy and did not produce anti-GH antibodies.

3.5.2. Autosomal Dominant Isolated Growth Hormone Deficiency A third type of IGHD (IGHD II) has an autosomal dominant mode of inheritance. Patients diagnosed with IGHD II have a single affected parent and respond well to rhGH. Patients differ in the severity of GH deficiency and their propensity for the development of hypoglycemia (25). Most of the IGHD II GH1 gene defects reported to date are mutations that alter splicing of GH mRNA and cause skipping of exon 3 (Table 1).

Table 2

Known Genes Causing MODY

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