Type II Isolated Growth Hormone Deficiency

PROM

Also Known As:

Isolated Growth Hormone Deficiency, Type II; Growth Hormone Deficiency, Isolated, Autosomal Dominant; IGHD II; IGHD2; Pituitary Dwarfism Due To Isolated Growth Hormone Deficiency, Autosomal Dominant

Networked: 26 relevant articles (1 outcomes, 2 trials/studies)

Relationship Network

Disease Context: Research Results

Related Diseases

1.	Type II Isolated Growth Hormone Deficiency
2.	Pituitary Dwarfism

Experts

1.	Phillips, John A: 6 articles (06/2011 - 02/2002)
2.	Eblé, Andrée: 5 articles (12/2015 - 12/2005)
3.	Mullis, Primus E: 5 articles (06/2010 - 02/2002)
4.	Flück, Christa E: 4 articles (01/2017 - 02/2010)
5.	Patton, James G: 4 articles (12/2009 - 07/2003)
6.	Robinson, Iain C A F: 4 articles (02/2008 - 07/2003)
7.	Godi, Michela: 3 articles (06/2010 - 03/2006)
8.	Lochmatter, Didier: 3 articles (06/2010 - 01/2007)
9.	Miletta, Maria Consolata: 2 articles (01/2017 - 12/2015)
10.	Mullis, Primus-E: 2 articles (01/2017 - 12/2015)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to Type II Isolated Growth Hormone Deficiency:

1.	Proteins (Proteins, Gene)FDA Link 06/01/2010 - "In conclusion, our results support the hypothesis that after GHRH stimulation, the severity of IGHD II depends on the position of splice site mutation leading to the production of increasing amounts of 17.5-kDa protein, which reduces the storage and secretion of wt-GH in the most severely affected cases. " 11/01/2007 - "To shed more light on the cellular and molecular basis of IGHD II, we established and analysed diverse clones of the rat somatotrophic cell line GH(4)C(1) stably expressing either wt-hGH, del(32-71)-hGH, or both proteins concomitantly. " 11/01/1994 - "In contrast the T-->C IGHD II mutant allele product retains these sequences and is transported to secretory granules where it can interact with the normal allele product producing a dominant-negative effect at the protein level." 11/01/1994 - "DNA sequencing of the GH1 genes of the first family (IGHD II) demonstrated heterozygosity for a T-->C transition in the sixth base of the donor splice site of intron III. 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. Interestingly, analysis of the transcripts derived from the mutant IGHD II allele revealed that the sequences corresponding to exon III were absent due to an exon skip that causes the loss of amino acids 32-71 from the mature GH protein. " 03/01/2005 - "Isolated GH deficiency type II (IGHD II) is mainly caused by heterozygous splice site mutations of GH-1 leading to the disruption of one disulfide bridge (Cys53-Cys165) and to the loss of amino acids (aa) 32-71, which comprise the complete loop between alpha-helices 1 and 2. The mutant GH protein exerts a dominant negative effect on wild-type (wt) GH secretion by unclear mechanisms. "
2.	DNA (Deoxyribonucleic Acid)IBA 12/01/2009 - "Members of the same IGHD II kindred were genotyped for the GH1 E3+1 G/A mutation by DNA sequencing. " 12/01/1995 - "Our finding of exon 3 skipping in transcripts of the + 1G-->A mutant allele is identical to our previous report of a different sixth base transition (+6T-->C) mutation of the IVS 3 donor splice site that also causes IGHD II. Microsatellite analysis of an affected subjects' DNA from each of the three nonrelated kindreds indicates that the + 1G-->A mutation arose independently in each family. " 11/01/1994 - "DNA sequencing of the GH1 genes of the first family (IGHD II) demonstrated heterozygosity for a T-->C transition in the sixth base of the donor splice site of intron III. 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. Interestingly, analysis of the transcripts derived from the mutant IGHD II allele revealed that the sequences corresponding to exon III were absent due to an exon skip that causes the loss of amino acids 32-71 from the mature GH protein. "
3.	Amino Acids FDA Link 11/01/2007 - "Autosomal dominant isolated growth hormone deficiency type II (IGHD II) is mainly caused by splice site mutations of the GH-1 gene, leading to deletion of amino acids 32-71 of the human growth hormone (hGH). " 11/01/1994 - "DNA sequencing of the GH1 genes of the first family (IGHD II) demonstrated heterozygosity for a T-->C transition in the sixth base of the donor splice site of intron III. 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. Interestingly, analysis of the transcripts derived from the mutant IGHD II allele revealed that the sequences corresponding to exon III were absent due to an exon skip that causes the loss of amino acids 32-71 from the mature GH protein. " 03/01/2005 - "Isolated GH deficiency type II (IGHD II) is mainly caused by heterozygous splice site mutations of GH-1 leading to the disruption of one disulfide bridge (Cys53-Cys165) and to the loss of amino acids (aa) 32-71, which comprise the complete loop between alpha-helices 1 and 2. The mutant GH protein exerts a dominant negative effect on wild-type (wt) GH secretion by unclear mechanisms. "
4.	Janus Kinase 2IBA 02/01/2010 - "AtT-20 cells coexpressing both wt-GH and GH-R178H showed a reduced GH secretion after forskolin stimulation compared with the cells expressing only wt-GH, supporting the diagnosis of IGHD II. Because reduced GH concentrations found in the circulation of our untreated patient could not totally explain her severe short stature, functional characterization of the GH-R178H performed by studies of GH receptor binding and activation of the Janus kinase-2/signal transducer and activator of transcription-5 pathway revealed a reduced binding affinity of GH-R178H for GH receptor and signaling compared with the wt-GH. "
5.	ColforsinIBA 02/01/2010 - "AtT-20 cells coexpressing both wt-GH and GH-R178H showed a reduced GH secretion after forskolin stimulation compared with the cells expressing only wt-GH, supporting the diagnosis of IGHD II. Because reduced GH concentrations found in the circulation of our untreated patient could not totally explain her severe short stature, functional characterization of the GH-R178H performed by studies of GH receptor binding and activation of the Janus kinase-2/signal transducer and activator of transcription-5 pathway revealed a reduced binding affinity of GH-R178H for GH receptor and signaling compared with the wt-GH. "
6.	Protein Isoforms (Isoforms)IBA 12/01/2008 - "For IGHD II, only exon skipping leads to production of the dominant-negative isoform, with increasing skipping correlating with increasing disease severity." 02/01/2008 - "Here, we have used delivery of short hairpin RNAs to rescue a murine model of IGHD II by specifically targeting transcripts encoding the 17.5-kDa isoform using RNA interference. " 12/01/2005 - "Our results show that specific and detailed analyses of the different mutations identified in IGHD II may shed light on the different mechanisms of secretory pathophysiology, and may provide a better explanation of the range of clinical features associated with GH missense isoforms. " 07/01/2003 - "We also show that splicing enhancer mutations that weaken exon 3 recognition produce variable amounts of the 17.5-kDa isoform, a result which could potentially explain the clinical variability observed in IGHD II. Non-canonical splicing mutations that disrupt splicing enhancers, such as those illustrated here, demonstrate the importance of enhancer elements in regulating alternative splicing to prevent human disease." 06/01/2010 - "An autosomal dominant form of isolated GH deficiency (IGHD II) can result from heterozygous splice site mutations that weaken recognition of exon 3 leading to aberrant splicing of GH-1 transcripts and production of a dominant-negative 17.5-kDa GH isoform. "
7.	Human Growth Hormone (Saizen)FDA LinkGeneric 08/29/2008 - "The majority of mutations that cause isolated growth hormone deficiency type II are the result of aberrant splicing of transcripts encoding human growth hormone. " 11/01/2007 - "Mutant and misfolded human growth hormone is rapidly degraded through the proteasomal degradation pathway in a cellular model for isolated growth hormone deficiency type II." 12/01/2008 - "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). " 07/01/2003 - "Isolated growth hormone deficiency type II (IGHD II) is characterized by short stature due to dominant-negative mutations of the human growth hormone gene (GH1). " 11/01/2007 - "Autosomal dominant isolated growth hormone deficiency type II (IGHD II) is mainly caused by splice site mutations of the GH-1 gene, leading to deletion of amino acids 32-71 of the human growth hormone (hGH). "
8.	Hormones (Hormone)IBA 11/01/2019 - "Our IGHD2 model mice exhibited growth retardation along with intact cellular architecture and mildly activated endoplasmic reticulum stress in the pituitary gland, caused by decreased GH-releasing hormone receptor (Ghrhr) and Gh gene promoter activities. " 07/01/2003 - "It is, therefore, important to understand the regulation of GH1 splicing and why its perturbation causes IGHD II. We demonstrate that dual splicing enhancers are required to ensure exon 3 definition to produce full-length 22-kDa hormone. " 12/01/2009 - "Dominant-negative GH1 mutations cause familial isolated growth hormone deficiency type II (IGHD II), which is characterized by GH deficiency, occasional multiple anterior pituitary hormone deficiencies, and anterior pituitary hypoplasia. " 06/01/2011 - "Dominant-negative growth hormone gene (GH1) mutations cause familial isolated growth hormone deficiency type II (IGHD II), which is characterized by GH deficiency, occasional multiple anterior pituitary hormone deficiencies, and anterior pituitary hypoplasia. "
9.	Growth Hormone (Somatotropin)IBA 01/15/2017 - "Isolated growth hormone deficiency type II (IGHD II) is a rare genetic splicing disorder characterized by reduced growth hormone (GH) secretion and short stature. " 07/01/2003 - "Disruption of exon definition produces a dominant-negative growth hormone isoform that causes somatotroph death and IGHD II." 06/01/2011 - "Dominant-negative growth hormone gene (GH1) mutations cause familial isolated growth hormone deficiency type II (IGHD II), which is characterized by GH deficiency, occasional multiple anterior pituitary hormone deficiencies, and anterior pituitary hypoplasia. "
10.	Messenger RNA (mRNA)IBA 03/01/2006 - "The IVS3 del+56-77 mutation, causing IGHD II in this family, has two separate effects on mRNA processing: 1) exon 3 skipping, analogous to most described cases of IGHD II, an effect likely caused by the reduction in size of the IVS3, and 2) partial or total exon 4 skipping, as a result of the removal of the BPS." 12/01/1995 - "Our data indicate that 1) + 1G-->A IVS 3 mutations perturb GH mRNA splicing and cause IGHD II; and 2) these mutations can present as de novo GHD cases." 02/01/2002 - "Familial isolated GH deficiency type II (IGHD II) is caused, in some cases, by heterogeneous IVS3 mutations that affect GH mRNA splicing. " 12/01/1995 - "Familial isolated GH deficiency type II (IGHD-II) is an autosomal dominant disorder that has been previously shown in some patients to be caused by heterogeneous GH gene defects that affect GH messenger RNA (mRNA) splicing. "

Therapies and Procedures

1.	Transplantation 01/01/2020 - "Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (≥7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. "
2.	Therapeutics 01/15/2017 - "Several avenues for alternative IGHD II therapy will be discussed including the use of small interfering RNA (siRNA) and short hairpin RNA (shRNA) constructs that specifically target the exon 3-deleted transcripts as well as the application of histone deacetylase inhibitors (HDACi) and antisense oligonucleotides (AONs) to enhance full-length GH-1 transcription, correct GH-1 exon 3 splicing and manipulate GH pathway."
3.	Injections 01/15/2017 - "At present, patients suffering from IGHD II are treated with daily injections of recombinant human GH (rhGH) in order to reach normal height. "