Multi-omics Investigations in Endocrine Systems and Their Clinical Implications.

Innovative techniques such as the "omics" can be a powerful tool for the understanding of intracellular pathways involved in homeostasis maintenance and identification of new potential therapeutic targets against endocrine-metabolic disorders. Over the last decades, proteomics has been extensively applied in the study of a wide variety of human diseases, including those involving the endocrine system. Among the most endocrine-related disorders investigated by proteomics in humans are diabetes mellitus and thyroid, pituitary, and reproductive system disorders. In diabetes, proteins implicated in insulin signaling, glucose metabolism, and ß-cell activity have been investigated. In thyroid diseases, protein expression alterations were described in thyroid malignancies and autoimmune thyroid illnesses. Additionally, proteomics has been used to investigate the variations in protein expression in adrenal cancers and conditions, including Cushing's syndrome and Addison's disease. Pituitary tumors and disorders including acromegaly and hypopituitarism have been studied using proteomics to examine changes in protein expression. Reproductive problems such as polycystic ovarian syndrome and endometriosis are two examples of conditions where alterations in protein expression have been studied using proteomics. Proteomics has, in general, shed light on the molecular underpinnings of many endocrine-related illnesses and revealed promising biomarkers for both their detection and treatment. The capacity of proteomics to thoroughly and objectively examine complex protein mixtures is one of its main benefits. Mass spectrometry (MS) is a widely used method that identifies and measures proteins based on their mass-to-charge ratio and their fragmentation pattern. MS can perform the separation of proteins according to their physicochemical characteristics, such as hydrophobicity, charge, and size, in combination with liquid chromatography. Other proteomics techniques include protein arrays, which enable the simultaneous identification of several proteins in a single assay, and two-dimensional gel electrophoresis (2D-DIGE), which divides proteins depending on their isoelectric point and molecular weight. This chapter aims to summarize the most relevant proteomics data from targeted tissues, as well as the daily rhythmic variation of relevant biomarkers in both physiological and pathophysiological conditions within the involved endocrine system, especially because the actual modern lifestyle constantly imposes a chronic unentrained condition, which virtually affects all the circadian clock systems within human's body, being also correlated with innumerous endocrine-metabolic diseases.

Biallelic splicing variants in the nucleolar 60S assembly factor RBM28 cause the ribosomopathy ANE syndrome.

Alopecia, neurologic defects, and endocrinopathy (ANE) syndrome is a rare ribosomopathy known to be caused by a p.(Leu351Pro) variant in the essential, conserved, nucleolar large ribosomal subunit (60S) assembly factor RBM28. We report the second family of ANE syndrome to date and a female pediatric ANE syndrome patient. The patient presented with alopecia, craniofacial malformations, hypoplastic pituitary, and hair and skin abnormalities. Unlike the previously reported patients with the p.(Leu351Pro) RBM28 variant, this ANE syndrome patient possesses biallelic precursor messenger RNA (pre-mRNA) splicing variants at the 5' splice sites of exon 5 (ΔE5) and exon 8 (ΔE8) of RBM28 (NM_018077.2:c.[541+1_541+2delinsA]; [946G > T]). In silico analyses and minigene splicing experiments in cells indicate that each splice variant specifically causes skipping of its respective mutant exon. Because the ΔE5 variant results in an in-frame 31 amino acid deletion (p.(Asp150_Lys180del)) in RBM28 while the ΔE8 variant leads to a premature stop codon in exon 9, we predicted that the ΔE5 variant would produce partially functional RBM28 but the ΔE8 variant would not produce functional protein. Using a yeast model, we demonstrate that the ΔE5 variant does indeed lead to reduced overall growth and large subunit ribosomal RNA (rRNA) production and pre-rRNA processing. In contrast, the ΔE8 variant is comparably null, implying that the partially functional ΔE5 RBM28 protein enables survival but precludes correct development. This discovery further defines the underlying molecular pathology of ANE syndrome to include genetic variants that cause aberrant splicing in RBM28 pre-mRNA and highlights the centrality of nucleolar processes in human genetic disease.

IDDB: a comprehensive resource featuring genes, variants and characteristics associated with infertility.

Infertility is a complex multifactorial disease that affects up to 10% of couples across the world. However, many mechanisms of infertility remain unclear due to the lack of studies based on systematic knowledge, leading to ineffective treatment and/or transmission of genetic defects to offspring. Here, we developed an infertility disease database to provide a comprehensive resource featuring various factors involved in infertility. Features in the current IDDB version were manually curated as follows: (i) a total of 307 infertility-associated genes in human and 1348 genes associated with reproductive disorder in 9 model organisms; (ii) a total of 202 chromosomal abnormalities leading to human infertility, including aneuploidies and structural variants; and (iii) a total of 2078 pathogenic variants from infertility patients' samples across 60 different diseases causing infertility. Additionally, the characteristics of clinically diagnosed infertility patients (i.e. causative variants, laboratory indexes and clinical manifestations) were collected. To the best of our knowledge, the IDDB is the first infertility database serving as a systematic resource for biologists to decipher infertility mechanisms and for clinicians to achieve better diagnosis/treatment of patients from disease phenotype to genetic factors. The IDDB is freely available at http://mdl.shsmu.edu.cn/IDDB/.

Pharmacological Interventions Targeting Pain in Fibrous Dysplasia/McCune-Albright Syndrome.

Fibrous dysplasia (FD) is a rare, non-inherited bone disease occurring following a somatic gain-of-function R201 missense mutation of the guanine-nucleotide binding protein alpha subunit stimulating activity polypeptide 1 (GNAS) gene. The spectrum of the disease ranges from a single FD lesion to a combination with extraskeletal features; an amalgamation with café-au-lait skin hyperpigmentation, precocious puberty, and other endocrinopathies defines McCune-Albright Syndrome (MAS). Pain in FD/MAS represents one of the most prominent aspects of the disease and one of the most challenging to treat-an outcome driven by (i) the heterogeneous nature of FD/MAS, (ii) the variable presentation of pain phenotypes (i.e., craniofacial vs. musculoskeletal pain), (iii) a lack of studies probing pain mechanisms, and (iv) a lack of rigorously validated analgesic strategies in FD/MAS. At present, a range of pharmacotherapies are prescribed to patients with FD/MAS to mitigate skeletal disease activity, as well as pain. We analyze evidence guiding the current use of bisphosphonates, denosumab, and other therapies in FD/MAS, and also discuss the potential underlying pharmacological mechanisms by which pain relief may be achieved. Furthermore, we highlight the range of presentation of pain in individual cases of FD/MAS to further describe the difficulties associated with employing effective pain treatment in FD/MAS. Potential next steps toward identifying and validating effective pain treatments in FD/MAS are discussed, such as employing randomized control trials and probing new pain pathways in this rare bone disease.

Endocrine Disorders in a Newborn with Heterozygous Galactosemia, Down Syndrome and Complex Cardiac Malformation: Case Report.

Down syndrome is the most common chromosomal abnormality diagnosed in newborn babies. Infants with Down syndrome have characteristic dysmorphic features and can have neuropsychiatric disorders, cardiovascular diseases, gastrointestinal abnormalities, eye problems, hearing loss, endocrine and hematologic disorders, and many other health issues. We present the case of a newborn with Down syndrome. The infant was a female, born at term through c-section. She was diagnosed before birth with a complex congenital malformation. In the first few days of life, the newborn was stable. In her 10th day of life, she started to show respiratory distress, persistent respiratory acidosis, and persistent severe hyponatremia, and required intubation and mechanical ventilation. Due to her rapid deterioration our team decided to do a screening for metabolic disorders. The screening was positive for heterozygous Duarte variant galactosemia. Further testing on possible metabolic and endocrinologic issues that can be associated with Down syndrome was performed, leading to hypoaldosteronism and hypothyroidism diagnoses. The case was challenging for our team because the infant also had multiple metabolic and hormonal deficiencies. Newborns with Down syndrome often require a multidisciplinary team, as besides congenital cardiac malformations they can have metabolic and hormonal deficiencies that can negatively impact their short- and long-term prognosis.

A practical guide to genetic testing in endocrinology.

Rapid advances in sequencing technology have led to significant improvements in genomic analysis, resulting in increased understanding of the molecular basis of many endocrine conditions. Genomic testing for rare disease is being integrated into everyday clinical practice, as the importance of confirming a genetic diagnosis earlier in a patient's pathway helps direct their clinical care and specialized management. In England, the new nationally commissioned Genomic Medicine Service has started to deliver testing for rare and inherited disease and cancer somatic tissue via seven Genomic Laboratory Hubs. The range of genetic tests, technology employed and eligibility criteria for patient testing are all defined in the National Genomic Test Directory. This review provides practical guidance on how to access genomic testing for endocrine disease, how to interpret and relay results, and details how genetic counselling can help integrate results into ongoing care of the individual and their family. This article discusses general principles as well as specifics related to the process of genomic testing in England. We illustrate mainstream genetic testing with a clinical scenario involving an individual with inherited endocrine neoplasia, followed by a generic description of the different steps involved, including informed consent to proceed to diagnostic testing. Most genetic tests analyse multiple genes simultaneously by next-generation sequencing, and variant interpretation may yield not only pathogenic explanatory results, but also ambiguous outcomes, with variants of unknown significance or incidental findings. Delivery of results and posttest genetic counselling are therefore key components of integrating genetic testing into routine endocrine care.

Polymorphisms of Vitamin D Receptor and the Effect on Metabolic and Endocrine Abnormalities in Polycystic Ovary Syndrome: A Review.

Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorder in women of reproductive age. Vitamin D and its receptor are thought to play an important role in PCOS susceptibility, although the impact of vitamin D receptor (VDR) polymorphisms on the hormonal and metabolic profile is still controversial. A literature search in PubMed and Embase was performed up to September 2020 for case-control studies in women suffering from PCOS, with outcome related to VDR polymorphisms effect on metabolic/endocrine disturbances. We have found 16 eligible studies including 2566 women with PCOS and 2430 controls. ApaI polymorphism seemed to be associated with hyperandrogenism in both Asian and Caucasian population. FokI variant was correlated with metabolic/endocrine parameters especially in Asian population, while a relation between Cdx2 genotypes and insulin sensitivity was observed in both ethnicities. VDR polymorphisms have an important role in PCOS development and related hormonal and metabolic abnormalities. Few case-control studies analysed the interaction between VDR variants and metabolic/endocrine parameters with the majority of the articles focused on the Asian region. Further research on various ethnic populations with larger sample size are still needed for a definitive conclusion, in order to allow early diagnosis and prevention of PCOS comorbidities.

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Evolutionary coupling analysis identifies the impact of disease-associated variants at less-conserved sites.

Genome-wide association studies have discovered a large number of genetic variants in human patients with the disease. Thus, predicting the impact of these variants is important for sorting disease-associated variants (DVs) from neutral variants. Current methods to predict the mutational impacts depend on evolutionary conservation at the mutation site, which is determined using homologous sequences and based on the assumption that variants at well-conserved sites have high impacts. However, many DVs at less-conserved but functionally important sites cannot be predicted by the current methods. Here, we present a method to find DVs at less-conserved sites by predicting the mutational impacts using evolutionary coupling analysis. Functionally important and evolutionarily coupled sites often have compensatory variants on cooperative sites to avoid loss of function. We found that our method identified known intolerant variants in a diverse group of proteins. Furthermore, at less-conserved sites, we identified DVs that were not identified using conservation-based methods. These newly identified DVs were frequently found at protein interaction interfaces, where species-specific mutations often alter interaction specificity. This work presents a means to identify less-conserved DVs and provides insight into the relationship between evolutionarily coupled sites and human DVs.

The Kynurenine Pathway-New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies.

The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells' differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies-type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis.

Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects.

Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.

New era of therapy for endocrine autoimmune disorders.

The new era of immune and reconstitution therapy of autoimmune disorders is ongoing. However, endocrine autoimmune diseases comprise a group of elaborating pathologies where the development of new treatment strategies remains slow. Substitution of the missing hormones is still standard practice, taking care of the devastating symptoms but not the cause of disease. As our knowledge of the genetic contribution to the aetiology of endocrine disorders increases and early diagnostic tools are available, it is now possible to identify persons at risk before they acquire full-blown disease. This review summarizes current knowledge and treatment of endocrine autoimmune disorders, focusing on type 1 diabetes, Addison's disease, autoimmune thyroid diseases and primary ovarian insufficiency. We explore which new therapies might be used in the different stages of the disease, focus on legalized therapy and elaborate on the ongoing clinical studies for these diseases and the research front, before hypothesizing on the way ahead.

Family history of diabetes mellitus and long-term endocrine morbidity of the offspring.

Background: Little is known regarding the long-term outcomes of offsprings to non-diabetic mothers with family history of diabetes mellitus (FHDM).Objective: The aim of the study was to determine whether being born to a non-diabetic mother with FHDM increases the risk for long-term endocrine morbidity.Methods: This is a population-based cohort study, comparing long-term endocrine morbidity between offspring born to non-diabetic mothers with and without FHDM. The Kaplan-Meier survival curve was used to compare cumulative morbidity incidence. Cox proportional hazards model was performed to control for confounders.Results: During the study period, 208,728 children met the inclusion criteria. Using a Kaplan-Meier survival curve, offspring born to non-diabetic mothers with a FHDM had higher cumulative incidence of endocrine morbidity compared to their counterparts without FHDM (Log rank test p = .014). Using a Cox model, controlling for confounders, being born to a non-diabetic mother with FHDM was an independent risk factor for long-term endocrine morbidity of the offspring (adjusted HR = 1.24, 95%CI 1.001-1.54; p = .043).Conclusion: Being born to a non-diabetic mother with a FHDM is independently associated with higher risk for long-term endocrine morbidity of the offspring.

Genetics of Equine Endocrine and Metabolic Disease.

A role for a genetic contribution to equine metabolic syndrome (EMS) and pars pituitary intermedia dysfunction (PPID) has been hypothesized. Heritability estimates of EMS biochemical measurements were consistent with moderately to highly heritable traits. Further, genome-wide association analyses have identified hundreds of regions of the genome contributing to EMS and candidate variants have been identified. The genetics of PPID has not yet been proven. Continued research for the specific genetic risk factors for both EMS and PPID is crucial for gaining a better understanding of the pathophysiology of both conditions and allowing development of genetic tests.

Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease: Case and Review.

We report three brothers born to consanguineous parents of Syrian descent, with a homozygous novel c.324G>A (p.W108*) mutation in PTRH2 that encodes peptidyl-tRNA hydrolase 2, causing infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We describe the core clinical features of postnatal microcephaly, motor and language delay with regression, ataxia, and hearing loss. Additional features include epileptic seizures, pancreatic insufficiency, and peripheral neuropathy. Clinical phenotyping enabled a targeted approach to the investigation and identification of a novel homozygous nonsense mutation in PTRH2, c.324G>A (p.W108*). We compare our patients with those recently described and review the current literature for IMNEPD.

Compte-rendu d'un cas de maladie infantile multi-systémique neurologique-endocrinienne-pancréatique. Nous voulons nous pencher ici sur le cas de trois frères nés de parents consanguins d'origine syrienne et donnant à voir une mutation homozygote c.324G>A (p.W108*) du gène PTRH2 rarement vue. Ce gène est responsable d'encoder la protéine peptidyl-tRNA hydrolase 2. Un encodage déficient causera chez des enfants une maladie multi-systémique neurologique-endocrinienne-pancréatique. Dans cet article, nous entendons décrire les aspects cliniques principaux de la microcéphalie postnatale, à savoir des délais et des régressions sur le plan du développement moteur et langagier mais aussi de l'ataxie et de la perte auditive. D'autres aspects cliniques sont également abordés, notamment des crises épileptiques, l'insuffisance pancréatique et une neuropathie périphérique. À cet égard, des outils de phénotypage clinique nous ont permis de compter sur une approche de recherche et d'identification ciblée en ce qui regarde la mutation non-sens évoquée ci-dessus. Enfin, nous voulons comparer nos jeunes patients à d'autres récemment décrits et passer en revue la littérature scientifique actuelle qui porte sur la maladie infantile multi-systémique neurologique-endocrinienne-pancréatique.

A de novo KMT2D mutation in a girl with Kabuki syndrome associated with endocrine symptoms: a case report.

BACKGROUND: Kabuki syndrome is characterized by distinctive facial features and varying degrees of growth retardation. It leads to malformations in skeletal, urogenital and cardiac structures; moreover, endocrine conditions such as premature thelarche, precocious puberty, growth hormone deficiency, diabetes insipidus, thyroid dysfunction and obesity have been reported. Kabuki syndrome is caused by a heterozygous mutation in the KMT2D or KDM6A genes. CASE PRESENTATION: An 11-year-old girl with the typical facial features of Kabuki syndrome visited our hospital due to her short stature. She was found to have the de novo heterozygous mutation of c.8200C > T, p(Arg2734*) in exon 32 of the KMT2D gene and was diagnosed with Kabuki syndrome. The patient also exhibited endocrine abnormalities such as a constitutional delay of puberty, transiently congenial hypothyroidism, obesity and growth hormone deficiency. CONCLUSIONS: This is a case of a mutation in the KMT2D gene in a girl with Kabuki syndrome who presented with endocrine symptoms (constitutional delay of puberty, hypothyroidism, obesity and growth hormone deficiency).

Gain-of-function mutations in G-protein-coupled receptor genes associated with human endocrine disorders.

The human genome encodes more than 700 G-protein-coupled receptors (GPCRs), many of which are involved in hormone secretion. To date, more than 100 gain-of-function (activating) mutations in at least ten genes for GPCRs, in addition to several loss-of-function mutations, have been implicated in human endocrine disorders. Previously reported gain-of-function GPCR mutations comprise various missense substitutions, frameshift mutations, intragenic inframe deletions and copy-number gains. Such mutations appear in both germline and somatic tumour cells, and lead to various hormonal abnormalities reflecting excessive receptor activity. Phenotypic consequences of these mutations include distinctive endocrine syndromes, as well as relatively common hormonal abnormalities. Such mutations encode hyperfunctioning receptors with increased constitutive activity, broadened ligand specificity, increased ligand sensitivity and/or delayed receptor desensitization. Furthermore, recent studies proposed a paradoxical gain-of-function mechanism caused by inactive GPCR mutants. Molecular diagnosis of GPCR activating mutations serves to improve the clinical management of mutation-positive patients. This review aims to introduce new aspects regarding gain-of-function mutations in GPCR genes associated with endocrine disorders.

Clock genes alterations and endocrine disorders.

BACKGROUND: Various endocrine signals oscillate over the 24-hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock. DESIGN: We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases. RESULTS: Various human single nucleotide polymorphisms of brain and muscle ARNT-like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue-specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio-melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue-specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers. CONCLUSIONS: Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue-specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.

The Activation Mechanism of Glycoprotein Hormone Receptors with Implications in the Cause and Therapy of Endocrine Diseases.

Glycoprotein hormones (GPHs) are the main regulators of the pituitary-thyroid and pituitary-gonadal axes. Selective interaction between GPHs and their cognate G protein-coupled receptors ensure specificity in GPH signaling. The mechanisms of how these hormones activate glycoprotein hormone receptors (GPHRs) or how mutations and autoantibodies can alter receptor function were unclear. Based on the hypothesis that GPHRs contain an internal agonist, we systematically screened peptide libraries derived from the ectodomain for agonistic activity on the receptors. We show that a peptide (p10) derived from a conserved sequence in the C-terminal part of the extracellular N terminus can activate all GPHRs in vitro and in GPHR-expressing tissues. Inactivating mutations in this conserved region or in p10 can inhibit activation of the thyroid-stimulating hormone receptor by autoantibodies. Our data suggest an activation mechanism where, upon extracellular ligand binding, this intramolecular agonist isomerizes and induces structural changes in the 7-transmembrane helix domain, triggering G protein activation. This mechanism can explain the pathophysiology of activating autoantibodies and several mutations causing endocrine dysfunctions such as Graves disease and hypo- and hyperthyroidism. Our findings highlight an evolutionarily conserved activation mechanism of GPHRs and will further promote the development of specific ligands useful to treat Graves disease and other dysfunctions of GPHRs.

Reproductive endocrine phenotypes relating to CHD7 mutations in humans.

Mutations in the gene CHD7 cause CHARGE syndrome, a rare multi-organ syndromic disorder. Gonadal defects are common in individuals with CHARGE syndrome (seen in ∼60-80% of cases) and represent the letter "G" in the CHARGE syndrome acronym. The gonadal defect in CHARGE syndrome results from congenital deficiency of the hypothalamic hormone Gonadotropin-releasing hormone (GnRH), which manifests clinically as pubertal failure and infertility, and biochemically as hypogonadotropic hypogonadism (low sex steroid hormone levels with inappropriately normal or low gonadotropin levels). In addition to the gonadal endocrine abnormalities, in a small minority of individuals with CHARGE, additional endocrine defects including growth hormone deficiency, multiple pituitary hormone deficits and primary hypothyroidism may also be seen. CHD7 mutations disrupt the targeting of olfactory axons and the migration of GnRH-synthesizing neurons during embryonic development, resulting in congenital idiopathic hypogonadotropic hypogonadism (IHH) and anosmia (or hyposmia), two features that define human Kallmann syndrome. Since Kallmann syndrome is one of the constituent phenotypes within CHARGE, recent studies have investigated the role of CHD7 mutations in individuals with IHH and established that deleterious missense mutations in CHD7 are associated with Kallmann syndrome as well as normosmic form of IHH. These missense mutations affect the ATPase and nucleosome remodeling activities of the CHD7 protein. These observations suggest that CHD7 protein function is critical for the ontogeny of GnRH neurons and neuroendocrine regulation of GnRH secretion.