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The American Journal of the Medical... Jun 2018
Topics: Fanconi Anemia; Humans; Laron Syndrome
PubMed: 29891046
DOI: 10.1016/j.amjms.2018.01.014 -
Xenotransplantation Mar 2021Xenotransplantation research has made considerable progress in recent years, largely through the increasing availability of pigs with multiple genetic modifications,... (Review)
Review
Xenotransplantation research has made considerable progress in recent years, largely through the increasing availability of pigs with multiple genetic modifications, effective immunosuppressive therapy, and anti-inflammatory therapy to protect pig tissues from the primate immune and inflammatory responses and correct molecular incompatibilities. Further study is required regarding identification and investigation of physiological incompatibilities. Although the exact cause remains uncertain, we and others have observed relatively rapid growth of kidney xenografts after transplantation into nonhuman primates (NHPs). There has also been some evidence of growth, or at least ventricular hypertrophy, of the pig heart after orthotopic transplantation into NHPs. Rapid growth could be problematic, particularly with regard to the heart within the relatively restricted confines of the chest. It has been suggested that the problem of rapid growth of the pig organ after transplantation could be resolved by growth hormone receptor (GHR) gene knockout in the pig. The GHR, although most well-known for regulating growth, has many other biological functions, including regulating metabolism and controlling physiological processes. Genetically modified GHRKO pigs have recently become available. We provide data on their growth compared to comparable pigs that do not include GHRKO, and we have reviewed the literature regarding the effect of GHRKO, and its relevance to xenotransplantation.
Topics: Animals; Animals, Genetically Modified; Graft Rejection; Heterografts; Receptors, Somatotropin; Swine; Transplantation, Heterologous; Transplants
PubMed: 33058285
DOI: 10.1111/xen.12652 -
Pediatric Endocrinology Reviews : PER Jan 2006Laron syndrome (LS) or primary GH insensitivity is a unique human model to study the effects of congenital IGF-I deficiency. Within our cohort of 63 patients with LS, 15... (Review)
Review
Laron syndrome (LS) or primary GH insensitivity is a unique human model to study the effects of congenital IGF-I deficiency. Within our cohort of 63 patients with LS, 15 female patients were regularly followed since birth or infancy, throughout puberty. We observed that they were short at birth, with small genitalia and gonads -- during puberty, developed delayed puberty but eventually reached between 16 and 19 1/2 years full sexual development. Reproduction is unaffected at a young adult age. It is concluded that IGF-I in concert with the sex hormones has a modulatory but not essential function on female sexual development and maturation.
Topics: Adult; Body Height; Female; Genitalia, Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Puberty, Delayed; Receptors, Somatotropin
PubMed: 16641857
DOI: No ID Found -
Biomolecules Mar 2023Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations...
Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations in the growth hormone receptor gene (). A -knockout (-KO) pig was developed as a model for LS, which displays many of the same features as humans with LS-like transient juvenile hypoglycemia. This study aimed to investigate the effects of impaired GHR signaling on immune functions and immunometabolism in -KO pigs. GHR are located on various cell types of the immune system. Therefore, we investigated lymphocyte subsets, proliferative and respiratory capacity of peripheral blood mononuclear cells (PBMCs), proteome profiles of CD4 and CD4 lymphocytes and IFN-α serum levels between wild-type (WT) controls and -KO pigs, which revealed significant differences in the relative proportion of the CD4CD8α subpopulation and in IFN-α levels. We detected no significant difference in the respiratory capacity and the capacity for polyclonal stimulation in PBMCs between the two groups. But proteome analysis of CD4 and CD4 lymphocyte populations revealed multiple significant protein abundance differences between -KO and WT pigs, involving pathways related to amino acid metabolism, beta-oxidation of fatty acids, insulin secretion signaling, and oxidative phosphorylation. This study highlights the potential use of -KO pigs as a model for studying the effects of impaired GHR signaling on immune functions.
Topics: Humans; Animals; Swine; Receptors, Somatotropin; Laron Syndrome; Leukocytes, Mononuclear; Proteome; Growth Hormone
PubMed: 37189345
DOI: 10.3390/biom13040597 -
European Archives of... Feb 2012The aim of this prospective clinical study was to test auditory function in patients with Laron syndrome, either untreated or treated with insulin-like growth factor I...
The aim of this prospective clinical study was to test auditory function in patients with Laron syndrome, either untreated or treated with insulin-like growth factor I (IGF-I). The study group consisted of 11 patients with Laron syndrome: 5 untreated adults, 5 children and young adults treated with replacement IGF-I starting at bone age <2 years, and 1 adolescent who started replacement therapy at bone age 4.6 years. The auditory evaluation included pure tone and speech audiometry, tympanometry and acoustic reflexes, otoacoustic emissions, loudness dynamics, auditory brain stem responses and a hyperacusis questionnaire. All untreated patients and the patient who started treatment late had various degrees of sensorineural hearing loss and auditory hypersensitivity; acoustic middle ear reflexes were absent in most of them. All treated children had normal hearing and no auditory hypersensitivity; most had recordable middle ear acoustic reflexes. In conclusion, auditory defects seem to be associated with Laron syndrome and may be prevented by starting treatment with IGF-I at an early developmental age.
Topics: Acoustic Impedance Tests; Adolescent; Age Determination by Skeleton; Audiometry, Pure-Tone; Audiometry, Speech; Child; Child, Preschool; Evoked Potentials, Auditory, Brain Stem; Female; Hearing Loss, Sensorineural; Humans; Hyperacusis; Infant; Insulin-Like Growth Factor I; Laron Syndrome; Loudness Perception; Male; Otoacoustic Emissions, Spontaneous; Prospective Studies; Reflex, Acoustic; Secondary Prevention; Young Adult
PubMed: 21735352
DOI: 10.1007/s00405-011-1668-x -
Trends in Endocrinology and Metabolism:... Sep 1998In the decade since the cloning and sequencing of the growth hormone receptor (GHR) and the recognition that the circulating GH-binding protein (GHBP) is structurally...
In the decade since the cloning and sequencing of the growth hormone receptor (GHR) and the recognition that the circulating GH-binding protein (GHBP) is structurally identical to the extracellular domain of the GHR, 34 mutations have been described. These include one deletion, eight nonsense mutations, eleven missense mutations, four frameshift mutations and ten splice mutations. More than half of the 131 patients with Laron syndrome whose molecular defects have been identified comprise the Ecuadorian cohort who share a single splice mutation. Variable expression of different homozygous or compound heterozygous defects of the GHR is no greater than the variation within a genetically homogeneous population. Some features, such as birth size and intelligence, are unlikely to be affected by GHRD. Greater understanding of the genetics, physiology, and clinical expression of abnormalities in the GH-GHR-IGF-I (insulin-like growth factor I) axis necessitates a reconsideration of the classification of GH insensitivity (GHI).
PubMed: 18406284
DOI: 10.1016/s1043-2760(98)00070-8 -
Journal of Medical Case Reports Jul 2011Primary growth hormone resistance or growth hormone insensitivity syndrome, also known as Laron syndrome, is a hereditary disease caused by deletions or different types...
INTRODUCTION
Primary growth hormone resistance or growth hormone insensitivity syndrome, also known as Laron syndrome, is a hereditary disease caused by deletions or different types of mutations in the growth hormone receptor gene or by post-receptor defects. This disorder is characterized by a clinical appearance of severe growth hormone deficiency with high levels of circulating growth hormone in contrast to low serum insulin-like growth factor 1 values.
CASE PRESENTATION
We report the case of a 15-year-old Caucasian girl who was diagnosed with Silver-Russell syndrome at the age of four and a half years. Recombinant growth hormone was administered for 18 months without an appropriate increase in growth velocity. At the age of seven years, her serum growth hormone levels were high, and an insulin-like growth factor 1 generation test did not increase insulin-like growth factor 1 levels (baseline insulin-like growth factor 1 levels, 52 μg/L; reference range, 75 μg/L to 365 μg/L; and peak, 76 μg/L and 50 μg/L after 12 and 84 hours, respectively, from baseline). The genetic analysis showed that the patient was homozygous for the R217X mutation in the growth hormone receptor gene, which is characteristic of Laron syndrome. On the basis of these results, the diagnosis of primary growth hormone insensitivity syndrome was made, and recombinant insulin-like growth factor 1 therapy was initiated. The patient's treatment was well tolerated, but unexplained central hypothyroidism occurred at the age of 12.9 years. At the age of 15 years, when the patient's sexual development was almost completed and her menstrual cycle occurred irregularly, her height was 129.8 cm, which is 4.71 standard deviations below the median for normal girls her age.
CONCLUSION
The most important functional tests for the diagnosis of growth hormone insensitivity are the insulin-like growth factor 1 generation test and genetic analysis. Currently, the only effective treatment is daily administration of recombinant insulin-like growth factor 1 starting from early childhood. However, these patients show a dramatically impaired final height. In our case, unexplained central hypothyroidism occurred during treatment.
PubMed: 21745362
DOI: 10.1186/1752-1947-5-301 -
Proceedings of the National Academy of... Nov 1997Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been...
Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR/BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR/BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans.
Topics: Animals; Carrier Proteins; Disease Models, Animal; Fertility; Gene Targeting; Growth Disorders; Growth Hormone; Humans; Mice; Mice, Knockout; Receptors, Somatotropin
PubMed: 9371826
DOI: 10.1073/pnas.94.24.13215 -
Journal of Translational Medicine Feb 2018Laron syndrome is an autosomal disease resulting from mutations in the growth hormone receptor (GHR) gene. The only therapeutic treatment for Laron syndrome is...
BACKGROUND
Laron syndrome is an autosomal disease resulting from mutations in the growth hormone receptor (GHR) gene. The only therapeutic treatment for Laron syndrome is recombinant insulin-like growth factor I (IGF-I), which has been shown to have various side effects. The improved Laron syndrome models are important for better understanding the pathogenesis of the disease and developing corresponding therapeutics. Pigs have become attractive biomedical models for human condition due to similarities in anatomy, physiology, and metabolism relative to humans, which could serve as an appropriate model for Laron syndrome.
METHODS
To further improve the GHR knockout (GHRKO) efficiency and explore the feasibility of precise DNA deletion at targeted sites, the dual-sgRNAs/Cas9 system was designed to target GHR exon 3 in pig fetal fibroblasts (PFFs). The vectors encoding sgRNAs and Cas9 were co-transfected into PFFs by electroporation and GHRKO cell lines were established by single cell cloning culture. Two biallelic knockout cell lines were selected as the donor cell line for somatic cell nuclear transfer for the generation of GHRKO pigs. The genotype of colonies, cloned fetuses and piglets were identified by T7 endonuclease I (T7ENI) assay and sequencing. The GHR expression in the fibroblasts and piglets was analyzed by confocal microscopy, quantitative polymerase chain reaction (q-PCR), western blotting (WB) and immunohistochemical (IHC) staining. The phenotype of GHRKO pigs was recapitulated through level detection of IGF-I and glucose, and measurement of body weight and body size. GHRKO F1 generation were generated by crossing with wild-type pigs, and their genotype was detected by T7ENI assay and sequencing. GHRKO F2 generation was obtained via self-cross of GHRKO F1 pigs. Their genotypes of GHRKO F2 generation was also detected by Sanger sequencing.
RESULTS
In total, 19 of 20 single-cell colonies exhibited biallelic modified GHR (95%), and the efficiency of DNA deletion mediated by dual-sgRNAs/Cas9 was as high as 90% in 40 GHR alleles of 20 single-cell colonies. Two types of GHR allelic single-cell colonies (GHR, GHR) were selected as donor cells for the generation of GHRKO pigs. The reconstructed embryos were transferred into 15 recipient gilts, resulting in 15 GHRKO newborn piglets and 2 fetuses. The GHRKO pigs exhibited slow growth rates and small body sizes. From birth to 13 months old, the average body weight of wild-type pigs varied from 0.6 to 89.5 kg, but that of GHRKO pigs varied from only 0.9 to 37.0 kg. Biochemically, the knockout pigs exhibited decreased serum levels of IGF-I and glucose. Furthermore, the GHRKO pigs had normal reproduction ability, as eighteen GHRKO F1 piglets were obtained via mating a GHRKO pig with wild-type pigs and five GHRKO F2 piglets were obtained by self-cross of F1 generation, indicating that modified GHR alleles can pass to the next generation via germline transmission.
CONCLUSION
The dual-sgRNAs/Cas9 is a reliable system for DNA deletion and that GHRKO pigs conform to typical phenotypes of those observed in Laron patients, suggesting that these pigs could serve as an appropriate model for Laron syndrome.
Topics: Animals; Base Sequence; CRISPR-Associated Protein 9; DNA; Disease Models, Animal; Embryo, Mammalian; Fetus; Fibroblasts; Gene Knockout Techniques; Germ Cells; Growth and Development; Laron Syndrome; Nuclear Transfer Techniques; Receptors, Somatotropin; Swine; RNA, Guide, CRISPR-Cas Systems
PubMed: 29482569
DOI: 10.1186/s12967-018-1409-7 -
Endokrynologia Polska 2017Short stature is the main problem that paediatric endocrinologists have to grapple with. Endocrine disorders account for only 5% of patients with short stature, but this... (Review)
Review
Short stature is the main problem that paediatric endocrinologists have to grapple with. Endocrine disorders account for only 5% of patients with short stature, but this is still one of the most common causes of reports to the endocrine clinic and hospitalisation in the endocrine department. A properly functioning growth hormone/insulin-like growth factor (GH/IGF) axis is one of the most important factors in proper growth. A lot of genetic defects in this axis lead to syndromes marked by impaired growth, like Laron syndrome, muta-tions in the STAT5B, insulin-like growth factor 1 (IGF1), and insulin-like growth factor 1 receptor (IGF1R) and mutations in the acid labile subunit (ALS). Two proteases important for the proper functioning of the GH/IGF axis: pregnancy-associated plasma protein-A (PAPP-A) and pregnancy-associated plasma protein-A2 (PAPP-A2), have been described. The first description of the new syndrome of growth failure associated with mutation in the PAPP-A2 gene was given by Andrew Dauber et al. This review evaluates the current data concerning PAPP-A2 function, and particularly the effect of PAPP-A2 mutation on growth.
Topics: Animals; Female; Growth; Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Mice; Mutation; Pregnancy-Associated Plasma Protein-A
PubMed: 29238946
DOI: 10.5603/EP.a2017.0060