Advances in pharmacogenomics will also optimize the treatment of isolated growth hormone deficiency and other conditions associated with short stature, for which recombinant human growth hormone is a licensed therapy.
Long-term human growth hormone expression and partial phenotypic correction by plasmid-based gene therapy in an animal model of isolated growth hormone deficiency.
A heterozygous single base mutation in the human growth hormone (GH) gene (GH-1) was identified in a family presenting with isolated GH deficiency type II (IGHD II).
In the present report we describe a novel 456G>A heterozygous mutation of splicing of the last base of the 3'-acceptor splice site of exon 4 within the GH1 in a 4.2-year old, extremely short (-5.32 height sDs) girl with congenital IGHD. the mutation involves a highly conserved GGGgtg sequence of the exon 4/IVs4 boundary region of the GH1 gene. the predicted effect of the 456 G>A mutation is perturbed splicing with possible skipping of exon 4 of the GH1 gene. the novel heterozygous 456 G>A mutation in exon 4 expands the spectrum of dominant negative splicing defects within the GH1 gene, responsible for congenital IGHD.
This study shows that GH-1 mutations are absent in 5/30 (16.6%) of the families with autosomal-dominant IGHD and raises the possibility that mutations in other gene(s) may be involved in IGHD with this mode of transmission.
Any genetic or acquired disorder that impairs GH secretion or action causes a pathological phenotype characterized by harmonic short stature with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency (CPHD).
G to A transition at position 6664 of the growth hormone (GH-1) gene results in the substitution of Arg183 by His (R183H) in the GH protein and causes a new form of autosomal dominant isolated GH deficiency (IGHD type II).
For comparison, we selected from a group of 66 MRI-studied GH-insufficient subjects diagnosed in our clinic, all children with severe IGHD (all GH peaks <4 microg/l) who had no GH-1 gene mutation, no first-grade relative with IGHD and no septo-optic dysplasia.
G to A transition at position 6664 of the GH-1 gene results in the substitution of Arg183 by His (R183H) in human GH protein and causes a new form of autosomal dominant isolated GH deficiency (type II).
Because de novo mutations appeared to have occurred in all three families analyzed in the present study and the presence or absence of these mutations can easily be tested by PCR and restriction enzyme digestion, not only the familial cases but also sporadic cases with IGHD should be examined for a possible mutation at the donor splice site of intron 3 in the GH-1 gene.
A high frequency of GH-1 gene alterations was found in families with IGHD type IA (8/12, 66.7%), whereas only a low frequency of GH-1 gene defects was present in all the other GH-deficient families (7/71, 9.9%).
Our finding that 3/23 (approximately 13%) Brazilian subjects had GH gene deletions agrees with previous studies of severe isolated GH deficiency subjects in other populations.
We carried out screening for mutations in the GH-1 gene in 29 sporadic Japanese subjects with severe Isolated Growth Hormone Deficiency (IGHD) by dideoxy fingerprinting (ddF).
Point mutations of the donor splice site of intron 3 of the human GH-1 gene cause autosomal dominant inherited isolated growth hormone deficiency (IGHD II).
The GH1 gene mutation in the second family (IGHD I) was found, in a previous study, to be a G-->C transversion altering the first base of the donor splice site of intron IV.
These growth curves constitute a model not only for primary, hereditary insulin-like growth factor-I (IGF-I) deficiency (Laron syndrome) but also for untreated secondary IGF-I deficiencies such as growth hormone gene deletion and idiopathic congenital isolated growth hormone deficiency.