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Gene Therapy Jun 2022
Topics: Genetic Therapy; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Mutation
PubMed: 35283485
DOI: 10.1038/s41434-022-00329-2 -
Gene Therapy Jun 2022The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The...
The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4-5-week-old Laron dwarf mice (GHR-/-) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 10 vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.
Topics: Animals; Disease Models, Animal; Genetic Therapy; Growth Hormone; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Mice; Receptors, Somatotropin
PubMed: 35105948
DOI: 10.1038/s41434-022-00313-w -
The Journal of Biological Chemistry Jan 2022SEC23B is one of two vertebrate paralogs of SEC23, a key component of the coat protein complex II vesicles. Complete deficiency of SEC23B in mice leads to perinatal...
SEC23B is one of two vertebrate paralogs of SEC23, a key component of the coat protein complex II vesicles. Complete deficiency of SEC23B in mice leads to perinatal death caused by massive degeneration of professional secretory tissues. However, functions of SEC23B in postnatal mice and outside professional secretory tissues are unclear. In this study, we generated a Sec23b KO mouse and a knockin (KI) mouse with the E109K mutation, the most common human mutation in congenital dyserythropoietic anemia type II patients. We found that E109K mutation led to decreases in SEC23B levels and protein mislocalization. However, Sec23b mice showed no obvious abnormalities. Sec23b hemizygosity (Sec23b) was partially lethal, with only half of expected hemizygous mice surviving past weaning. Surviving Sec23b mice exhibited exocrine insufficiency, increased endoplasmic reticulum stress and apoptosis in the pancreas, and phenotypes consistent with chronic pancreatitis. Sec23b mice had mild to moderate anemia without other typical congenital dyserythropoietic anemia type II features, likely resulting from exocrine insufficiency. Moreover, Sec23b mice exhibited severe growth restriction accompanied by growth hormone (GH) insensitivity, reminiscent of Laron syndrome. Growth restriction is not associated with hepatocyte-specific Sec23b deletion, suggesting a nonliver origin of this phenotype. We propose that inflammation associated with chronic pancreatic deficiency may explain GH insensitivity in Sec23b mice. Our results reveal a genotype-phenotype correlation in SEC23B deficiency and indicate that pancreatic acinar is most sensitive to SEC23B deficiency in adult mice. The Sec23b mice provide a novel model of chronic pancreatitis and growth retardation with GH insensitivity.
Topics: Anemia, Dyserythropoietic, Congenital; Animals; Mice; Mutation, Missense; Pancreatitis, Chronic; Phenotype; Vesicular Transport Proteins
PubMed: 34954140
DOI: 10.1016/j.jbc.2021.101536 -
International Journal of Molecular... Dec 2021Ever since the discoveries that human hair follicles (HFs) display the functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis, exhibit elements of... (Review)
Review
Ever since the discoveries that human hair follicles (HFs) display the functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis, exhibit elements of the hypothalamic-pituitary-thyroid axis, and even generate melatonin and prolactin, human hair research has proven to be a treasure chest for the exploration of neurohormone functions. However, growth hormone (GH), one of the dominant neurohormones of human neuroendocrine physiology, remains to be fully explored in this context. This is interesting since it has long been appreciated clinically that excessive GH serum levels induce distinct human skin pathology. Acromegaly, or GH excess, is associated with hypertrichosis, excessive androgen-independent growth of body hair, and hirsutism in females, while dysfunctional GH receptor-mediated signaling (Laron syndrome) is associated with alopecia and prominent HF defects. The outer root sheath keratinocytes have recently been shown to express functional GH receptors. Furthermore, and contrary to its name, recombinant human GH is known to inhibit female human scalp HFs' growth ex vivo, likely via stimulating the expression of the catagen-inducing growth factor, TGF-β2. These limited available data encourage one to systematically explore the largely uncharted role of GH in human HF biology to uncover nonclassical functions of this core neurohormone in human skin physiology.
Topics: Female; Hair Follicle; Human Growth Hormone; Humans; Receptors, Somatotropin; Skin
PubMed: 34948002
DOI: 10.3390/ijms222413205 -
Hormone Research in Paediatrics 2022Consanguineous families have often played a role in the discovery of novel genes, especially in paediatric endocrinology. At this time, it has been estimated that over... (Review)
Review
Invaluable Role of Consanguinity in Providing Insight into Paediatric Endocrine Conditions: Lessons Learnt from Congenital Hyperinsulinism, Monogenic Diabetes, and Short Stature.
Consanguineous families have often played a role in the discovery of novel genes, especially in paediatric endocrinology. At this time, it has been estimated that over 8.5% of all children worldwide have consanguineous parents. Consanguinity is linked to demographic, cultural, and religious practises and is more common in some areas around the world than others. In children with endocrine conditions from consanguineous families, there is a greater probability that a single-gene condition with autosomal recessive inheritance is causative. From 1966 and the first description of Laron syndrome, through the discovery of the first KATP channel genes ABCC8 and KCNJ11 causing congenital hyperinsulinism (CHI) in the 1990s, to recent discoveries of mutations in YIPF5 as the first cause of monogenic diabetes due to the disruption of the endoplasmic reticulum (ER)-to-Golgi trafficking in the β-cell and increased ER stress; positive genetic findings in children from consanguinity have been important in elucidating novel genes and mechanisms of disease, thereby expanding knowledge into disease pathophysiology. The aim of this narrative review was to shed light on the lessons learned from consanguineous pedigrees with the help of 3 fundamental endocrine conditions that represent an evolving spectrum of pathophysiological complexity - from CHI, a typically single-cell condition, to monogenic diabetes which presents with uniform biochemical parameters (hyperglycaemia and glycosuria), despite varying aetiologies, up to the genetic regulation of human growth - the most complex developmental phenomenon.
Topics: Child; Congenital Hyperinsulinism; Consanguinity; Diabetes Mellitus; Dwarfism; Humans; KATP Channels; Mutation
PubMed: 34847552
DOI: 10.1159/000521210 -
International Journal of Biological... 2021Laron syndrome (LS) is an autosomal recessive genetic disease mainly caused by mutations in the human growth hormone receptor () gene. Previous studies have focused on...
Laron syndrome (LS) is an autosomal recessive genetic disease mainly caused by mutations in the human growth hormone receptor () gene. Previous studies have focused on mutant mice, but compared with LS patients, knockout (KO) mice exhibit differential lipid metabolism. To elucidate the relationship between mutation and lipid metabolism, the role of GHR in lipid metabolism was examined in KO pigs and hepatocytes transfected with si. We observed high levels of free fatty acids and hepatic steatosis in KO pigs, which recapitulates the abnormal lipid metabolism in LS patients. RNAseq analysis revealed that genes related to the fatty acid oxidation pathway were significantly altered in KO pigs. AHR, a transcription factor related to lipid metabolism, was significantly downregulated in GHR KO pigs and sitreated human hepatocytes. We found that AHR directly regulated fatty acid oxidation by directly binding to the promoters of ACOX1 and CPT1A and activating their expression. These data indicate that loss of GHR disturbs the ERK-AHR-ACOX1/CPT1A pathway and consequently leads to hepatic steatosis. Our results established AHR as a modulator of hepatic steatosis, thereby providing a therapeutic target for lipid metabolism disorder.
Topics: Animals; Body Weight; Carrier Proteins; Cell Line; Fatty Liver; Female; Gene Expression Regulation; Genotype; Glucose; Glucose Tolerance Test; Hepatocytes; Homeostasis; Humans; Lipid Metabolism; Male; Neoplasm Proteins; Receptors, Aryl Hydrocarbon; Signal Transduction; Swine
PubMed: 34803486
DOI: 10.7150/ijbs.64894 -
International Journal of Molecular... Nov 2021The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies,...
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies, including cancer. The GH-IGF1 hormonal system, in addition, has emerged as a major determinant of lifespan and healthspan. Laron syndrome (LS), the best characterized entity under the spectrum of the congenital IGF1 deficiencies, results from mutation of the GH receptor (GHR) gene, leading to dwarfism, obesity and other defects. Consistent with the key role of IGF1 in cellular proliferation, epidemiological studies have shown that LS patients are protected from cancer development. While reduced expression of components of the GH-IGF1 axis is associated with enhanced longevity in animal models, it is still unknown whether LS is associated with an increased lifespan. MicroRNAs (miRs) are endogenous short non-coding RNAs that regulate the expression of complementary mRNAs. While a number of miRs involved in the regulation of IGF components have been identified, no previous studies have investigated the differential expression of miRs in congenital IGF1 deficiencies. The present study was aimed at identifying miRs that are differentially expressed in LS and that might account for the phenotypic features of LS patients, including longevity. Our genomic analyses provide evidence that miR-132-3p was highly expressed in LS. In addition, we identified SIRT1, a member of the sirtuin family of histone deacetylases, as a target for negative regulation by miR-132-3p. The data was consistent with the notion that low concentrations of IGF1 in LS lead to elevated miR-132-3p levels, with ensuing reduction in SIRT1 gene expression. The impact of the IGF1-miR-132-3p-SIRT1 loop on aging merits further investigation.
Topics: 3' Untranslated Regions; Adult; Case-Control Studies; Cell Line; Cell Proliferation; Female; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Longevity; MicroRNAs; Middle Aged; Sirtuin 1; Up-Regulation
PubMed: 34769292
DOI: 10.3390/ijms222111861 -
Oxford Medical Case Reports Sep 2021Laron syndrome (LS) is a rare autosomal recessive disorder characterized by dwarfism and typical facial phenotype. This report is the first to present three cases of...
Laron syndrome (LS) is a rare autosomal recessive disorder characterized by dwarfism and typical facial phenotype. This report is the first to present three cases of Laron syndrome affecting three female siblings from Syria. The index case presented at age of 8.5 years with severe short stature: low level of Insulin-like growth factor 1 (IGF-1), elevated levels of fasting and post-stimulation growth hormone (GH), consistent with the diagnosis of Laron syndrome. At the age of 9.5 years, she developed non-autoimmune subclinical hypothyroidism treated with Levothyroxine, then she developed dyslipidemia at the age of 11.3 years. Later, we identified two female siblings of the patient with Laron syndrome. Laron syndrome is a rare genetic disease, reporting of new cases of this rare syndrome must encourage pediatricians to develop high clinical suspicion if faced with patients with very short stature and typical facial features.
PubMed: 34527252
DOI: 10.1093/omcr/omab079 -
Acta Bio-medica : Atenei Parmensis Sep 2021Hormone resistance is defined as a reduced or absence of target tissues responsiveness to a hormone, where the presentation is related to either a relative lack or...
Hormone resistance is defined as a reduced or absence of target tissues responsiveness to a hormone, where the presentation is related to either a relative lack or excess of hormones. Various disorders of hormone resistance were encountered including, Laron syndrome, nephrogenic diabetes insipidus, thyroid hormone resistance syndrome, pseudohypoparathyroidism, insulin resistance, familial glucocorticoid deficiency, pseudohypoaldosteronism, X linked hypophosphatemic rickets and androgen insensitivity syndrome. The article gives a summary that presents, in concentrated form, what the primary care physicians need to know about recognition, clinical presentation, diagnosis, and management of various hormone resistance in children.
Topics: Child; Diabetes Insipidus, Nephrogenic; Hormones; Humans; Insulin Resistance; Male; Physicians, Primary Care
PubMed: 34487068
DOI: 10.23750/abm.v92i4.11613