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The Journal of Clinical Endocrinology... Jul 2021Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.
CONTEXT
Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.
OBJECTIVE
This work aims to identify the genetic cause of growth failure in 3 "classical" GHI individuals.
METHODS
A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.
RESULTS
We identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation.
CONCLUSION
Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
PubMed: 34453441
DOI: 10.1210/clinem/dgab550 -
Endocrine Connections Aug 2021Animal studies suggest that insulin-like growth factor 1 (IGF1) may influence the function of the hypothalamus-pituitary-testicular axis, especially in childhood, but...
BACKGROUND
Animal studies suggest that insulin-like growth factor 1 (IGF1) may influence the function of the hypothalamus-pituitary-testicular axis, especially in childhood, but the evidence in humans is scanty. Laron syndrome, a human model of IGF1 deficiency, may help to solve this issue.
PURPOSE
This systematic review aims to analyze puberty onset and progression, testicular volume, gonadotropin, and total testosterone serum levels, sperm parameters and fertility, and penile length in patients with Laron syndrome.
METHODS
Specific keywords were used. All data on male patients with Laron syndrome were included.
RESULTS
Seventeen articles matched the inclusion criteria and were entered in the analysis, for a total of 125 male patients. Puberty was absent in 8.9% and delayed in 35.6% of untreated patients of pubertal age. After onset, the duration of the pubertal process was prolonged in 76.9% of untreated patients. The growth spurt was absent in 52.6% and delayed in 31.6% of untreated patients. The testicular volume was small in the two patients who did not receive any treatment. Treatment with IGF1 increased gonadotropin and testosterone serum levels in five out of five patients of pubertal age. No effect was found in four out of four patients younger than 5 years. No study reported data on sperm parameters and fertility. Micropenis occurred in 67.2% of patients.
CONCLUSION AND FUTURE PERSPECTIVES
Delayed puberty is common in patients with Laron syndrome. The growth hormone-IGF1 axis may influence the time of puberty onset. Serum levels of IGF1 should be investigated in children with delayed puberty, scarce progression of testicular growth, and/or micropenis. IGF1 levels might be measured in children with delayed puberty, poor testicular growth, and/or micropenis.
PubMed: 34319907
DOI: 10.1530/EC-21-0252 -
The Journal of Clinical Endocrinology... Jul 2021Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies.
CONTEXT
Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies.
OBJECTIVE
Identification of the genetic cause of growth failure in 3 'classical' GHI subjects.
DESIGN
A novel intronic GHR variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.
RESULTS
We identified a novel homozygous intronic GHR variant (g.5:42700940T>G, c.618 + 836T> G), 44bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C>T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a non-functional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following growth hormone stimulation.
CONCLUSION
Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
PubMed: 34318893
DOI: 10.1210/clinem/dgab550 -
Journal of Pediatric Endocrinology &... Oct 2021Laron syndrome (LS) is a disease caused by growth hormone receptor (GHR) defects. It is characterized by severe postnatal growth retardation and distinctive facial...
OBJECTIVES
Laron syndrome (LS) is a disease caused by growth hormone receptor (GHR) defects. It is characterized by severe postnatal growth retardation and distinctive facial features.
CASE PRESENTATION
In this case report, we describe the clinical and biochemical characteristics of two siblings with LS, a sister and a brother, and identify a homozygous c.344A> C (p.Asn115Thr) variant in GHR. The sister was 11 years 9 months old with a height of 127.5 cm (-3.86 SDS), and the brother was 14 years 10 months old with a height of 139 cm (-4.27 SDS). Their phenotype did not have features suggesting classical LS.
CONCLUSION
In the current literature, there are three cases with the same missense variant. Our cases differ from them in clinical (higher height SDS, mild dysmorphism including a broad forehead, malar hypoplasia, prominent columella and chin, thick lips) and biochemical characteristics. Here, we present the variable expressivity in the two siblings.
Topics: Adolescent; Carrier Proteins; Child; Female; Humans; Laron Syndrome; Male; Mutation, Missense; Patient Acuity; Phenotype; Polymorphism, Single Nucleotide; Receptors, Somatotropin; Siblings; Turkey
PubMed: 34218547
DOI: 10.1515/jpem-2021-0044 -
Cells Jun 2021Endometrial cancer is the most common gynecologic malignancy in Western countries. The insulin-like growth factor-1 (IGF1) axis has an important role in endometrial...
Endometrial cancer is the most common gynecologic malignancy in Western countries. The insulin-like growth factor-1 (IGF1) axis has an important role in endometrial cancer biology and emerged as a promising therapeutic target in oncology. However, there is an urgent need to identify biomarkers that may help in patient stratification and prognosis. Laron syndrome (LS) is a type of dwarfism that results from the mutation of the growth hormone receptor (GHR) gene, leading to congenital IGF1 deficiency. While high circulating IGF1 is regarded as a risk factor in cancer, epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide profilings conducted on LS-derived lymphoblastoid cells led to the identification of a series of genes whose over- or under-representation in this condition might be mechanistically linked to cancer protection. The olfactory receptor 5 subfamily H member 2 () was the top downregulated gene in LS, its expression level being 5.8-fold lower than in the control cells. In addition to their typical role in the olfactory epithelium, olfactory receptors (ORs) are expressed in multiple tissues and play non-classical roles in various pathologies, including cancer. The aim of our study was to investigate the regulation of gene expression by IGF1 in endometrial cancer. Data showed that IGF1 and insulin stimulate OR5H2 mRNA and the protein levels in uterine cancer cell lines expressing either a wild-type or a mutant p53. OR5H2 silencing led to IGF1R downregulation, with ensuing reductions in the downstream cytoplasmic mediators. In addition, OR5H2 knockdown reduced the proliferation rate and cell cycle progression. Analyses of olfr196 (the mouse orthologue of OR5H2) mRNA expression in animal models of GHR deficiency or GH overexpression corroborated the human data. In summary, OR5H2 emerged as a novel target for positive regulation by IGF1, with potential relevance in endometrial cancer.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cystadenocarcinoma, Serous; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Mice; Mice, Transgenic; Receptor, IGF Type 1; Receptors, Odorant; Signal Transduction
PubMed: 34204736
DOI: 10.3390/cells10061483 -
The Journal of Clinical Endocrinology... Oct 2021Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum...
CONTEXT
Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding.
OBJECTIVE
We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH-IGF-I axis defects.
METHODS
Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing, whole exome sequencing, array comparative genomic hybridization, and a targeted whole genome short stature gene panel.
RESULTS
Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH-IGF-I axis defects (GHR n = 40, IGFALS n = 4, IGFIR n = 1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n = 10) (OBSL1 n = 7, CUL7 n = 2, and CCDC8 n = 1), Noonan syndrome (n = 4) (PTPN11 n = 2, SOS1 n = 1, and SOS2 n = 1), Silver-Russell syndrome (n = 2) (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n = 10), and disorders not previously associated with GHI (n = 9) (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, and Bloom syndrome).
CONCLUSION
We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management.
Topics: Adolescent; Adult; Biomarkers; Body Height; Child; Child, Preschool; Comparative Genomic Hybridization; DNA Copy Number Variations; Female; Follow-Up Studies; Genetic Testing; Growth Disorders; Human Growth Hormone; Humans; Infant; Insulin-Like Growth Factor I; Laron Syndrome; Male; Prognosis; Young Adult
PubMed: 34136918
DOI: 10.1210/clinem/dgab437 -
Science Advances Jun 2021Recent studies have identified impaired type 2 alveolar epithelial cell (ATII) renewal in idiopathic pulmonary fibrosis (IPF) human organoids and severe fibrosis when...
Recent studies have identified impaired type 2 alveolar epithelial cell (ATII) renewal in idiopathic pulmonary fibrosis (IPF) human organoids and severe fibrosis when ATII is defective in mice. ATIIs function as progenitor cells and require supportive signals from the surrounding mesenchymal cells. The mechanisms by which mesenchymal cells promote ATII progenitor functions in lung fibrosis are incompletely understood. We identified growth hormone receptor (GHR) is mainly expressed in mesenchymal cells, and its expression is substantially decreased in IPF lungs. Higher levels of expression correlated with better lung function in patients with IPF. Profibrotic mesenchymal cells retarded ATII growth and were associated with suppressed vesicular expression. Vesicles enriched with promote ATII proliferation and diminished pulmonary fibrosis in mesenchymal -deficient mice. Our findings demonstrate a previously unidentified mesenchymal paracrine signaling coordinated by that is capable of supporting ATII progenitor cell renewal and limiting the severity of lung fibrosis.
Topics: Alveolar Epithelial Cells; Animals; Humans; Idiopathic Pulmonary Fibrosis; Laron Syndrome; Lung; Mice; Stem Cells
PubMed: 34108218
DOI: 10.1126/sciadv.abg6005 -
European Journal of Endocrinology Jul 2021The aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal... (Review)
Review
The aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups into two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provided additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, and increasing glucose levels with age. In the Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels; neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort nor in the animal models. A reduced beta-cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of puberty is reported. Reduced gluconeogenesis in GHRD is discussed to cause juvenile hypoglycemia and a counter-regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.
Topics: Age Factors; Animals; Animals, Genetically Modified; Cohort Studies; Disease Models, Animal; Ecuador; Humans; Hypoglycemia; Israel; Laron Syndrome; Mice; Mice, Knockout; Receptors, Somatotropin; Signal Transduction; Swine
PubMed: 34048365
DOI: 10.1530/EJE-21-0013 -
Frontiers in Endocrinology 2021Laron syndrome (LS) is a severe growth disorder caused by gene mutation or post-receptor pathways defect. The clinical features of these patients collected in our...
PURPOSE
Laron syndrome (LS) is a severe growth disorder caused by gene mutation or post-receptor pathways defect. The clinical features of these patients collected in our present study were summarized, gene variants were investigated and further functional verification was carried out.
METHODS
Four patients with LS were collected, their clinical characteristics were summarized, genomic DNA was extracted, and gene was amplified and sequenced. GHR wild type (GHR-WT) and mutant GHR expression plasmids were constructed, and transiently transfected into HepG2 cells and HEK293T cells to observe the subcellular distribution of the GHR protein by immunofluorescence and to determine the expression of GHR and its post-receptor signaling pathway changes by Western blotting.
RESULTS
All of the four patients were male, and the median height was -4.72 SDS. Four gene variants including c.587A>C (p.Y196S), c.766C>T (p.Q256*), c.808A>G (p.I270V) and c.1707-1710del (p.E570Afs*30) were identified, and the latter two were novel mutations. The results of mutant GHR plasmids transfection experiments and immunofluorescence assay showed that the subcellular distribution of GHR-Q256* and GHR-E570Afs*30 mutant proteins in HepG2 and HEK293T cells presented with a unique ring-like pattern, gathering around the nucleus, while GHR-Y196S mutant protein was evenly distributed on HepG2 cell membrane similar to GHR-WT. The GHR protein levels of HepG2 cells transiently transfected with GHR-Y196S, GHR-Q256* and GHR-E570Afs*30 were all significantly lower when compared with cells transfected with GHR-WT (P<0.05). Further mutant GHR post-receptor signal transduction investigation demonstrated that GH induced phosphorylated STAT5 levels of HepG2 cells transfected with three mutant plasmids were all significantly decreased in comparison with that of GHR-WT (P<0.05).
CONCLUSIONS
Two novel gene mutations (I270V and E570Afs*30) were found in our patients with LS. GHR mutations influenced the subcellular distribution and GHR protein levels, then led to the impaired post-receptor signal transduction, suggesting that the mutations contributed to the pathological condition of LS patients.
Topics: Adolescent; Carrier Proteins; Child; Child, Preschool; China; DNA Mutational Analysis; HEK293 Cells; Hep G2 Cells; Humans; Laron Syndrome; Male; Mutation
PubMed: 33912130
DOI: 10.3389/fendo.2021.605736 -
Seminars in Cell & Developmental Biology Jan 2022Sertoli cells (SCs) are immune privileged cells found in the testis that function to immunologically protect maturing germ cells from immune destruction. This immune... (Review)
Review
Sertoli cells (SCs) are immune privileged cells found in the testis that function to immunologically protect maturing germ cells from immune destruction. This immune protection is due to the blood-testis-barrier, which prevents infiltration of cytotoxic immune cells and antibodies, and SC production of immunomodulatory factors, that favor a tolerogenic environment. The ability of SCs to create an immune privileged environment has led to the exploration of their potential use in the treatment of various diseases. SCs have been utilized to create a tolerogenic ectopic microenvironment, to protect co-grafted cells, and to deliver therapeutic proteins through gene therapy. To date, numerous studies have reported the potential use of SCs for the treatment of diabetes, neurodegenerative disorders, and restoration of spermatogenesis. Additionally, SCs have been investigated as a delivery vehicle for therapeutic products to treat other diseases like Laron syndrome, muscular dystrophy, and infections. This review will provide an overview of these therapeutic applications.
Topics: Animals; Cell- and Tissue-Based Therapy; Humans; Male; Mice; Sertoli Cells
PubMed: 33910764
DOI: 10.1016/j.semcdb.2021.04.007