32 research outputs found
The Role of S-Palmitoylation of the Human Glucocorticoid Receptor (hGR) in Mediating the Nongenomic Glucocorticoid Actions
Background: Many rapid nongenomic glucocorticoid actions are mediated by membrane-bound glucocorticoid receptors (GRs). S-palmitoylation is a lipid post-translational modification that mediates the membrane localization of some steroid receptors. A highly homologous amino acid sequence (663YLCM KTLLL671) is present in the ligand-binding domain of hGRα, suggesting that hGRα might also undergo S-palmitoylation. Aim: To investigate the role of the motif 663YLCMKTLLL671 in membrane localization of the hGRα and in mediating rapid nongenomic glucocorticoid signaling. Methods and Results: We showed that the mutant receptors hGRαY663A, hGRαC665A and hGRαLL670/671AA, and the addition of the palmitoylation inhibitor 2-bromopalmitate did not prevent membrane localization of hGRα and co-localization with caveolin-1, and did not influence the biphasic activation of mitogen-activated protein kinase (MAPK) signaling pathway in the early time points. Finally, the hGRα was not shown to undergo S-palmitoylation. Conclusions: The motif 663YLCMKTLLL671 does not play a role in membrane localization of hGRα and does not mediate the nongenomic glucocorticoid actions.
Correction:Clinical and genetic characterization of chanarin-dorfman syndrome patients: first report of large deletions in the ABHD5 gene
AbstractFollowing the publication of this article [Redaelli C et al, Clinical and genetic characterization of Chanarin-Dorfman Syndrome patients: first report of large deletions in the ABHD5 gene. Orphanet J Rare Dis 2010; 5: 33.], it was clarified that the clinical follow-up of one of CDS family described in the manuscript was performed by Dr. Amalia Sertedaki and Talia Kakourou. The authorship of the article has been changed accordingly. The submitting authors would like to apologise to Amalia Sertedaki and Talia Kakourou for this error and they would like to thank Catherine Dacou-Voutetakis for underlining the problem
Recent advances in the molecular mechanisms causing primary generalized glucocorticoid resistance
Primary Generalized Glucocorticoid Resistance is a rare condition
characterized by generalized, partial, target tissue insensitivity to
glucocorticoids owing to inactivating mutations, insertions or deletions
in the human glucocorticoid receptor (hGR) gene (NR3C1). Recent advances
in molecular and structural biology have enabled us to elucidate the
molecular mechanisms of action of the mutant receptors and to understand
how certain conformational alterations of the defective hGRs result in
generalized glucocorticoid resistance. Furthermore, our ever-increasing
understanding of the molecular mechanisms of glucocorticoid action
indicates that the glucocorticoid signaling pathway is a stochastic
system that plays a fundamental role in maintaining both basal and
stress-related homeostasis. In this review, we summarize the clinical
manifestations and molecular pathogenesis of Primary Generalized
Glucocorticoid Resistance, we present our recent findings from the
functional characterization of three novel heterozygous point mutations
in the NR3C1 gene, and we discuss the diagnostic approach and
therapeutic management of the condition. When the condition is
suspected, we recommend sequencing analysis of the NR3C1 gene as well as
of other genes encoding proteins involved in the glucocorticoid signal
transduction. The tremendous progress of next-generation sequencing will
undoubtedly uncover novel hGR partners or cofactors
PROP1 gene mutations and pituitary size: A unique case of two consecutive cycles of enlargement and regression
Background: Pituitary enlargement, which can regress with time, has been
described in a number of PROP1-deficient patients. We report a
PROP1-deficient patient with a unique variation in pituitary size. Case
Description: A 4-year-old boy was first examined in 1989 for short
stature (- 2.3 standard deviation score). Growth hormone (GH)
insufficiency was confirmed, and human GH (hGH) therapy was initiated
and administered up to the age of 18.2 years. Levothyroxine was added 6
months after hGH initiation. Pituitary magnetic resonance imaging (MRI)
obtained when the patient was 5 years old showed an enlarged pituitary
gland, which grew larger by the age of 8.5 years and then regressed to
normal size by the time the patient was 9.8 years old. MRI when the
patient was 19 years old disclosed pituitary reenlargement, and another
3 years later indicated regression. On DNA analysis, the patient was
found to be homozygous for the mutation 301-302 Delta GA of the PROP1
gene. When the patient was 18.8 years old and asymptomatic, an impaired
cortisol response to glucagon was detected. Conclusions: Regression of
the pituitary enlargement in PROP1-deficient patients does not seem to
constitute an end stage with respect to pituitary pathology. Further
changes in pituitary morphology and size can be expected; therefore,
long-term followup with pituitary MRI is advised. Copyright (c) 2007 S.
Karger AG, Basel
Unravelling the Genetic Basis of Primary Aldosteronism
Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. Over the last decade, major breakthroughs have been made in the field of genetics underpinning PA. The advent and wide application of Next Generation Sequencing (NGS) technology led to the identification of several somatic and germline mutations associated with sporadic and familial forms of PA. Somatic mutations in ion-channel genes that participate in aldosterone biosynthesis, including KCNJ5, CACNA1D, ATP1A1, and ATP2B3, have been implicated in the development of aldosterone-producing adenomas (APAs). On the other hand, germline variants in CLCN2, KCNJ5, CACNA1H, and CACNA1D genes have been implicated in the pathogenesis of the familial forms of PA, FH-II, FH-III, and F-IV, as well as PA associated with seizures and neurological abnormalities. However, recent studies have shown that the prevalence of PA is higher than previously thought, indicating the need for an improvement of our diagnostic tools. Further research is required to recognize mild forms of PA and to investigate the underlying molecular mechanisms
Unravelling the Genetic Basis of Primary Aldosteronism
Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. Over the last decade, major breakthroughs have been made in the field of genetics underpinning PA. The advent and wide application of Next Generation Sequencing (NGS) technology led to the identification of several somatic and germline mutations associated with sporadic and familial forms of PA. Somatic mutations in ion-channel genes that participate in aldosterone biosynthesis, including KCNJ5, CACNA1D, ATP1A1, and ATP2B3, have been implicated in the development of aldosterone-producing adenomas (APAs). On the other hand, germline variants in CLCN2, KCNJ5, CACNA1H, and CACNA1D genes have been implicated in the pathogenesis of the familial forms of PA, FH-II, FH-III, and F-IV, as well as PA associated with seizures and neurological abnormalities. However, recent studies have shown that the prevalence of PA is higher than previously thought, indicating the need for an improvement of our diagnostic tools. Further research is required to recognize mild forms of PA and to investigate the underlying molecular mechanisms
PROP-1 gene mutations in a 63-year-old woman presenting with osteoporosis and hyperlipidaemia
PROP-1 gene mutations have been reported as a cause of combined
pituitary hormone deficiency. Physical and hormonal phenotypes of
affected individuals are variable. We report a 63-year-old female who
presented with osteoporosis. She was short, did not enter puberty
spontaneously and had primary amenorrhea. Biochemical evaluation
revealed secondary hypothyroidism and mixed hyperlipidaemia, while
dynamic testing of pituitary function was diagnostic of hypopituitarism.
Bone density in the lumbar spine disclosed osteoporosis. DNA analysis
showed that the patient was homozygote for the R73H mutation of the
PROP-1 gene. The unfavourable long-term course of an untreated patient
with PROP-1 gene mutation emphasizes the need for early aetiologic
classification and proper management and follow-up of patients with
short stature and/or disturbances of pubertal development
Aldosterone synthase deficiency type II: an unusual presentation of the first Greek case reported with confirmed genetic analysis
Objective. Aldosterone synthase deficiency (ASD) is a rare, autosomal recessive inherited disease with an overall clinical phenotype of failure to thrive, vomiting, severe dehydration, hyperkalemia, and hyponatremia. Mutations in the CYP11B2 gene encoding aldosterone synthase are responsible for the occurrence of ASD. Defects in CYP11B2 gene have only been reported in a limited number of cases worldwide. Due to this potential life-threatening risk, comprehensive hormonal investigation followed by genetic confirmation is essential for the clinical management of offsprings
A case of digenic maturity onset diabetes of the young with heterozygous variants in both HNF1A and HNF1B genes
Background: Maturity onset diabetes of the young (MODY) is the most
commonly reported form of monogenic diabetes in the pediatric
population. Only a few cases of digenic MODY have been reported up to
now. Case report: A female patient was diagnosed with diabetes at the
age of 7 years and was treated with insulin. A strong family history of
diabetes was present in the maternal side of the family. The patient
also presented hypomagnesemia, glomerulocystic kidney disease and a
bicornuate uterus. Genetic testing of the patient revealed that she was
a double heterozygous carrier of HNF1A gene variant c.685C > T;
(p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother
was a carrier of the same HNF1A variant. Conclusion: Digenic inheritance
of MODY pathogenic variants is probably more common than currently
reported in literature. The use of Next Generation Sequencing panels in
testing strategies for MODY could unmask such cases that would otherwise
remain undiagnosed
Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency
Combined pituitary hormone deficiency (CPHD) is characterized by deficiency of growth hormone and at least one other pituitary hormone. Pathogenic variants in more than 30 genes expressed during the development of the head, hypothalamus, and/or pituitary have been identified so far to cause genetic forms of CPHD. However, the etiology of around 85% of the cases remains unknown. The aim of this study was to unveil the genetic etiology of CPHD due to congenital hypopituitarism employing whole exome sequencing (WES) in two newborn patients, initially tested and found to be negative for PROP1, LHX3, LHX4 and HESX1 pathogenic variants by Sanger sequencing and for copy number variations by MLPA. In this study, the application of WES in these CPHD newborns revealed the presence of three different heterozygous gene variants in each patient. Specifically in patient 1, the variants BMP4; p.Ala42Pro, GNRH1; p.Arg73Ter and SRA1; p.Gln32Glu, and in patient 2, the SOX9; p.Val95Ile, HS6ST1; p.Arg306Gln, and IL17RD; p.Pro566Ser were identified as candidate gene variants. These findings further support the hypothesis that CPHD constitutes an oligogenic rather than a monogenic disease and that there is a genetic overlap between CPHD and congenital hypogonadotropic hypogonadism