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1.
Biochem Pharmacol ; 217: 115858, 2023 11.
Article in English | MEDLINE | ID: mdl-37863325

ABSTRACT

The CD40 receptor and its ligand CD154 are widely expressed in various immune-competent cells. Interaction of CD154 with CD40 is essential for B-cell growth, differentiation, and immunoglobulin class switching. Many other immune-competent cells involved in innate and adaptive immunity communicate through this co-stimulatory ligand-receptor dyad. CD40-CD154 interaction is involved in the pathogenesis of numerous inflammatory and autoimmune diseases. While CD40 and CD154 are membrane-bound proteins, their soluble counterparts are generated by proteolytic cleavage or alternative splicing. This review summarises current knowledge about the impact of single nucleotide polymorphisms in the human CD40 gene and compensatory changes in the plasma level of the soluble CD40 receptor (sCD40) isoform in related pro-inflammatory diseases. It discusses regulation patterns of the disintegrin metalloprotease ADAM17 function leading to ectodomain shedding of transmembrane proteins, such as pro-inflammatory adhesion molecules or CD40. The role of sCD40 as a potential biomarker for chronic inflammatory diseases will also be discussed.


Subject(s)
CD40 Antigens , CD40 Ligand , Humans , Ligands , CD40 Antigens/genetics , CD40 Antigens/metabolism , CD40 Ligand/genetics , CD40 Ligand/metabolism , Chronic Disease , Membrane Proteins
2.
Endocr Connect ; 12(12)2023 Dec 01.
Article in English | MEDLINE | ID: mdl-37855374

ABSTRACT

Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.

3.
Gynecol Obstet Fertil Senol ; 50(5): 402-408, 2022 05.
Article in French | MEDLINE | ID: mdl-34560302

ABSTRACT

Endocrine disruptor chemicals (EDCs) are ubiquitous contaminants in the environment, wildlife, and humans. During the last 20 years, several epidemiological, clinical and experimental studies have demonstrated the role of EDCs on the reduction of male and female fertility. The concept of foetal origins of adult disease is particularly topical in the field of reproduction. Moreover, exposure to EDCs during pregnancy has been shown to influence epigenetic programming of endocrine signalling and other important physiological pathways, and provided the basis for multi- and transgenerational transmission of adult diseases. However, the large panel of EDCs simultaneously present in the air, sol and water makes the quantification of human exposition still a challenge. Gas chromatography coupled with mass spectrometry, the measurement of total plasmatic hormonal bioactivity on stably transfected cell lines as well as the EDC analysis in hair samples are useful methods of evaluation. More recently, microRNAs analysis offers a new perspective in the comprehension of the mechanisms behind the modulation of cellular response to foetal or post-natal exposure to EDCs. They will help researchers and clinicians in identifying EDCs exposition markers and new therapeutic approaches in the future.


Subject(s)
Endocrine Disruptors , Adult , Endocrine Disruptors/adverse effects , Endocrine Disruptors/analysis , Female , Fertility , Humans , Male , Pregnancy , Reproduction
4.
Int J Mol Sci ; 22(7)2021 Apr 01.
Article in English | MEDLINE | ID: mdl-33915887

ABSTRACT

The methylation of adenosine in the N6 position (m6A) is a widely used modification of eukaryotic mRNAs. Its importance for the regulation of mRNA translation was put forward recently, essentially due to the ability of methylated mRNA to be translated in conditions of inhibited cap-dependent translation initiation, e.g., under stress. However, the peculiarities of translation initiation on m6A-modified mRNAs are not fully known. In this study, we used toeprinting and translation in a cell-free system to confirm that m6A-modified mRNAs can be translated in conditions of suppressed cap-dependent translation. We show for the first time that m6A-modified mRNAs display not only decreased elongation, but also a lower efficiency of translation initiation. Additionally, we report relative resistance of m6A-mRNA translation initiation in the absence of ATP and inhibited eIF4A activity. Our novel findings indicate that the scanning of m6A-modified leader sequences is performed by a noncanonical mechanism.


Subject(s)
Protein Biosynthesis , RNA, Messenger/metabolism , HEK293 Cells , Humans , Methylation
6.
Endocr Res ; 45(1): 32-40, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31394950

ABSTRACT

Purpose: Testotoxicosis is an autosomal dominant form of limited gonadotropin-independent precocious puberty in boys. It is caused by a heterozygous constitutively activating mutation of the LHCGR gene encoding the luteinizing/hormone receptor (LHR). Some twenty mutations of the LHCGR gene have been reported. Most of them are constitutive mutations isolated from blood leukocyte DNA, although others are somatic, found only in testicular tumoural tissue. In all the previously reported cases of these somatic mutations, the tumour, whether a nodular Leydig cell adenoma or hyperplasia, was easily visible on testicular ultrasonography. The aim of this study was to describe an unusual presentation of a patient with the clinical and hormonal characteristics of testotoxicosis but no well-circumscribed lesion at testicular ultrasonography.Materials and Methods: Molecular analysis of the LHCGR gene was performed by direct sequencing of DNA extracted from peripheral leucocytes and testicular biopsy.Results: Molecular analysis didn't find any LHR mutation in blood, whereas it revealed for the first time a somatic D578H mutation in testicular tissue despite no evidence of a nodular aspect at testis ultrasonography.Conclusions: This observation underlines the need to look for a somatic LHCGR gene mutation from the testicular biopsies of all boys with testotoxicosis with no constitutive LHCGR gene mutation identified from blood DNA, even in the absence of circumscribed testicular lesion at ultrasonography. In addition, based on the known link between LHR mutations and testicular tumourigenesis, yearly ultrasound monitoring of the testes should be considered for these patients.


Subject(s)
Puberty, Precocious/diagnostic imaging , Puberty, Precocious/genetics , Receptors, LH/genetics , Child , Humans , Male , Ultrasonography
7.
Clin Genet ; 92(1): 99-103, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28032338

ABSTRACT

Steroidogenic factor 1 (encoded by SF1/NR5A1) is a transcription factor with multiple target genes involved in the development and function of multiple steroidogenic and non-steroidogenic tissues. NR5A1 mutations lead to several phenotypes, including sex reversal, spermatogenesis failure, premature ovarian failure and adrenocortical insufficiency. The implication of NR5A1 mutations in spleen development anomalies was recently highlighted. We provide new evidence of this involvement, describing a novel heterozygous non-sense NR5A1 mutation in a 46,XY-DSD with polysplenia female proband and her father, who had hypospadias and asplenia.


Subject(s)
Adrenal Insufficiency/genetics , Hypospadias/genetics , Primary Ovarian Insufficiency/genetics , Steroidogenic Factor 1/genetics , Adolescent , Adrenal Insufficiency/pathology , Child , Female , Heterozygote , Humans , Hypospadias/pathology , Male , Mutation , Primary Ovarian Insufficiency/pathology , Sex Determination Processes/genetics , Spermatogenesis/genetics , Spleen/growth & development , Spleen/pathology
8.
Gynecol Obstet Fertil ; 44(11): 659-663, 2016 Nov.
Article in French | MEDLINE | ID: mdl-27751748

ABSTRACT

Participation in recreational physical activity is widely acknowledged to provide significant health benefits. Conversely, intense training imposes several constraints, such as intermittent or chronic metabolic and psychogenic training stressors and maintenance of very low body fat to maximize performance. Adolescent and adult athletic women are therefore at risk of overtraining and/or poor dietary intake, which may have several consequences for endocrine function particularly on hypothalamic-pituitary-gonadal axis. Female athletes, particularly those participating in sports needing leanness or low body weight, present a high prevalence of menstrual disorders with clinical manifestations ranging from delayed menarche, oligomenorrhea to primary and secondary amenorrhea. A high degree of variability according to the type of sport and the intensity of the practice is however observed. Exercise-related reproductive dysfunction may have some consequences for growth velocity and peak bone mass acquisition during adolescence and bone pathologies in adults. Recent findings highlight the endocrine role of adipose tissue and energy balance in the regulation of homeostasis and reproductive function. A better understanding of the mechanisms whereby intense training affects the endocrine systems may orient research to develop innovative strategies probably based on individualized nutritional approach to improve the medical care of these female athletes and protect their reproductive function.


Subject(s)
Bone Density/physiology , Exercise/physiology , Menstruation Disturbances/epidemiology , Sports , Adolescent , Amenorrhea , Body Composition , Diet , Female , Humans , Menarche/physiology , Puberty , Reproduction , Young Adult
9.
Andrology ; 4(2): 263-9, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26845730

ABSTRACT

Pubertal gynecomastia is a common condition observed in up to 65% of adolescent males. It is usually idiopathic and tends to regress within 1-2 years. In this descriptive cross-sectional study, we investigated 25 adolescent males with prominent (>B3) and/or persistent (>2 years) pubertal gynecomastia (P/PPG) to determine whether a hormonal/genetic defect might underline this condition. Endocrine investigation revealed the absence of hormonal disturbance for 18 boys (72%). Three patients presented Klinefelter syndrome and three a partial androgen insensitivity syndrome (PAIS) as a result of p.Ala646Asp and p.Ala45Gly mutations of the androgen receptor gene. The last patient showed a 17α-hydroxylase/17,20-lyase deficiency as a result of a compound heterozygous mutation of the CYP17A1 gene leading to p.Pro35Thr(P35T) and p.Arg239Stop(R239X) in the P450c17 protein. Enzymatic activity was analyzed: the mutant protein bearing the premature stop codon R239X showed a complete loss of 17α-hydroxylase and 17,20-lyase activity. The mutant P35T seemed to retain 15-20% of 17α-hydroxylase and about 8-10% of 17,20-lyase activity. This work demonstrates that P/PPG had an endocrine/genetic cause in 28% of our cases. PAIS may be expressed only by isolated gynecomastia as well as by 17α-hydroxylase/17,20-lyase deficiency. Isolated P/PPG is not always a 'physiological' condition and should thus be investigated through adequate endocrine and genetic investigations, even though larger studies are needed to better determine the real prevalence of genetic defects in such patients.


Subject(s)
Gynecomastia/genetics , Adolescent , Androgen-Insensitivity Syndrome/genetics , Androgen-Insensitivity Syndrome/metabolism , Cohort Studies , Cross-Sectional Studies , Gynecomastia/metabolism , Hormones/metabolism , Humans , Male , Mutation , Receptors, Androgen/genetics , Steroid 17-alpha-Hydroxylase/genetics , Transcriptome
10.
Horm Metab Res ; 48(3): 174-7, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26418163

ABSTRACT

Recent experimental data suggest that circulating serotonin interacts with bone metabolism, although this is less clear in humans. This study investigated whether serum serotonin interferes with bone metabolism in young women with anorexia nervosa (AN), a clinical model of energy deprivation. Serum serotonin, markers of bone turnover [osteocalcin (OC), procollagen type I N-terminal propeptide (PINP), type I-C telopeptide breakdown products (CTX)], leptin, soluble leptin receptor (sOB-R), and insulin-like growth factor-1 (IGF-1) and its binding protein (IGFBP-3) were assessed. Whole body, spine, hip, and radius areal bone mineral density BMD (aBMD) were assessed by dual-energy X-ray absorptiometry in 21 patients with AN and 19 age-matched controls. Serum serotonin, leptin, IGF-1, IGFBP-3, OC, PINP, and aBMD at all sites, radius excepted, were significantly reduced in AN whereas CTX and sOB-R were increased compared with controls. Serum serotonin levels were positively correlated with weight, body mass index, whole body fat mass, leptin, and IGF-1, and negatively with CTX for the entire population. Low serum serotonin levels are observed in patients with AN. Although no direct link between low serum serotonin levels and bone mass was identified in these patients, the negative relationship between serotonin and markers of bone resorption found in all population nevertheless suggests the implication of serotonin in bone metabolism. Impact of low serum serotonin on bone in AN warrants further studies.


Subject(s)
Anorexia Nervosa/blood , Bone Resorption/blood , Serotonin/blood , Adolescent , Anorexia Nervosa/complications , Anorexia Nervosa/physiopathology , Anthropometry , Bone Density , Bone Resorption/complications , Bone Resorption/physiopathology , Case-Control Studies , Female , Hormones , Humans
11.
Osteoporos Int ; 27(1): 135-46, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26245848

ABSTRACT

UNLABELLED: Low bone mass is a consequence of anorexia nervosa (AN). This study assessed the effects of energy deficiency on various bone and hormonal parameters. The interrelationships between energy deficiency and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit demineralisation and hormonal alterations in AN patients. INTRODUCTION: Low areal bone mineral density (aBMD) is a well-known consequence of AN. However, the impact of reduced energy expenditure on bone metabolism is unknown. This study assessed the effects of energy deficiency on bone remodelling and its potential interactions with glucose homeostasis and adipose tissue-derived hormones in AN, a clinical model for reduced energy expenditure. METHODS: Fifty women with AN and 50 age-matched controls (mean age 18.1 ± 2.7 and 18.0 ± 2.1 years, respectively) were enrolled. aBMD was determined with DXA. Resting energy expenditure (REEm), a marker of energy status, was indirectly assessed by calorimetry. Bone turnover markers, undercarboxylated osteocalcin (ucOC), parameters of glucose homeostasis, adipokines and growth factors were concomitantly evaluated. RESULTS: AN patients presented low aBMD at all bone sites. REEm, bone formation markers, ucOC, glucose, insulin, HOMA-IR, leptin and IGF-1 were significantly reduced, whereas the bone resorption marker, leptin receptor (sOB-R) and adiponectin were elevated in AN compared with CON. In AN patients, REEm was positively correlated with weight, BMI, whole body (WB) fat mass, WB fat-free soft tissue, markers of bone formation, glucose, insulin, HOMA-IR, leptin and IGF-1 and negatively correlated with the bone resorption marker and sOB-R. Biological parameters, aBMD excepted, appeared more affected by the weight variation in the last 6 months than by the disease duration. CONCLUSIONS: The strong interrelationships between REEm and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit short- and long-term bone demineralisation and hormonal alterations in AN patients.


Subject(s)
Adipokines/blood , Anorexia Nervosa/physiopathology , Blood Glucose/metabolism , Bone Remodeling/physiology , Energy Metabolism/physiology , Adolescent , Anorexia Nervosa/blood , Anorexia Nervosa/complications , Anthropometry/methods , Biomarkers/blood , Body Weight/physiology , Bone Density/physiology , Bone Diseases, Metabolic/blood , Bone Diseases, Metabolic/etiology , Bone Diseases, Metabolic/physiopathology , Case-Control Studies , Female , Homeostasis/physiology , Humans , Intercellular Signaling Peptides and Proteins/blood , Menstruation/physiology , Time Factors , Young Adult
12.
Cell Death Dis ; 6: e1736, 2015 May 07.
Article in English | MEDLINE | ID: mdl-25950466

ABSTRACT

ALK is a receptor tyrosine kinase with an oncogenic role in various types of human malignancies. Despite constitutive activation of the kinase through gene alterations, such as chromosomal translocation, gene amplification or mutation, treatments with kinase inhibitors invariably lead to the development of resistance. Aiming to develop new tools for ALK targeting, we took advantage of our previous demonstration identifying ALK as a dependence receptor, implying that in the absence of ligand the kinase-inactive ALK triggers or enhances apoptosis. Here, we synthesized peptides mimicking the proapoptotic domain of ALK and investigated their biological effects on tumor cells. We found that an ALK-derived peptide of 36 amino acids (P36) was cytotoxic for ALK-positive anaplastic large-cell lymphoma and neuroblastoma cell lines. In contrast, ALK-negative tumor cells and normal peripheral blood mononuclear cells were insensitive to P36. The cytotoxic effect was due to caspase-dependent apoptosis and required N-myristoylation of the peptide. Two P36-derived shorter peptides as well as a cyclic peptide also induced apoptosis. Surface plasmon resonance and mass spectrometry analysis of P36-interacting proteins from two responsive cell lines, Cost lymphoma and SH-SY5Y neuroblastoma, uncovered partners that could involve p53-dependent signaling and pre-mRNA splicing. Furthermore, siRNA-mediated knockdown of p53 rescued these cells from P36-induced apoptosis. Finally, we observed that a treatment combining P36 with the ALK-specific inhibitor crizotinib resulted in additive cytotoxicity. Therefore, ALK-derived peptides could represent a novel targeted therapy for ALK-positive tumors.


Subject(s)
Neoplasms/drug therapy , Neoplasms/enzymology , Peptide Fragments/pharmacology , Receptor Protein-Tyrosine Kinases/metabolism , Anaplastic Lymphoma Kinase , Apoptosis/drug effects , Apoptosis/physiology , Biomimetic Materials/pharmacology , Cell Line, Tumor , Crizotinib , HeLa Cells , Humans , Jurkat Cells , Neoplasms/pathology , Neuroblastoma/drug therapy , Neuroblastoma/enzymology , Neuroblastoma/pathology , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Signal Transduction
13.
Andrologia ; 46(6): 703-6, 2014 Aug.
Article in English | MEDLINE | ID: mdl-23808476

ABSTRACT

We report on a case of a man with familial, X-linked, partial androgen insensitivity, in whom a new point mutation in the androgen receptor (AR) ligand-binding domain (causing a valine-to-alanine substitution at codon 686) was identified. High-dose prolonged testosterone therapy resulted in marked progression in patient's appearance and great improvement in sperm count and characteristics. In combination with intracytoplasmic microinjection, treatment resulted in fertility. This is believed to be the first report of such a case. This case supports high-dose testosterone therapeutic trial in this condition. Furthermore, it underscores the possibility of achieving fertility with current endocrine and assisted reproduction modalities, making some of these X-linked AR mutations paternally transmissible.


Subject(s)
Androgen-Insensitivity Syndrome/drug therapy , Androgen-Insensitivity Syndrome/genetics , Point Mutation , Receptors, Androgen/genetics , Testosterone/therapeutic use , Adult , Amino Acid Substitution , Androgen-Insensitivity Syndrome/pathology , Female , Humans , Infant, Newborn , Infertility, Male/genetics , Infertility, Male/pathology , Infertility, Male/therapy , Male , Pregnancy , Semen Analysis , Sperm Count , Sperm Injections, Intracytoplasmic , Testosterone/administration & dosage
14.
Int J Androl ; 35(3): 253-64, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22372605

ABSTRACT

Exposure to endocrine-disrupting chemicals (EDCs) has been suggested to contribute to the increasing trends of external genital malformation in male newborns. In Northeastern Brazil, the poor sanitary conditions found in the favelas encourage the widespread use of pesticides. This 2-year study of a total birth cohort of full-term male newborns in the regional hospitals of Campina Grande (Paraíba, Brazil) sought to (1) accurately establish for the first time the incidences of neonatal male genital malformations, (2) investigate the endocrine and genetic aetiologies of these malformations, and (3) evaluate their associations with possible prenatal exposure to EDCs. A total of 2710 male newborns were explored for cryptorchidism, hypospadias and micropenis. Cases were referred to the Pediatric Endocrine Clinic for endocrine and genetic investigations, and all parents were interviewed about their environmental/occupational exposure to EDCs before/during pregnancy by paediatric endocrinologists using a detailed questionnaire. We observed 56 cases of genital malformation (2.07%), including 23 cryptorchidism (0.85%), 15 hypospadias (0.55%), and 18 micropenis (0.66%). All cases exhibited normal/subnormal testosterone production and none presented androgen receptor or 5α-reductase gene mutation. More than 92% of these newborns presented foetal contamination by EDCs, as their mothers reported daily domestic use of pesticides (i.e., DDT) and other EDCs. Most of these undervirilized male newborns presented additional EDC contamination, as 80.36% of the mothers and 58.63% of the fathers reported paid or unpaid work that entailed the use of pesticides and other EDCs before/during pregnancy for the mothers and around the time of fertilization for the fathers. The high rate of micropenis in our population associated with an elevated percentage of parental environmental/occupational exposure to EDCs before/during pregnancy indicates that foetal contamination may be a risk factor for the development of male external genital malformation.


Subject(s)
Endocrine Disruptors/toxicity , Environmental Exposure/adverse effects , Genital Diseases, Male/epidemiology , Pesticides/toxicity , Brazil/epidemiology , Cryptorchidism/epidemiology , Female , Humans , Hypospadias/epidemiology , Infant , Infant, Newborn , Male , Maternal Exposure/adverse effects , Paternal Exposure/adverse effects , Penis/abnormalities , Pregnancy , Prevalence
15.
Oncogene ; 31(6): 694-705, 2012 Feb 09.
Article in English | MEDLINE | ID: mdl-21725365

ABSTRACT

Therapeutic resistance of acute myeloid leukemia stem cells, enriched in the CD34(+)38(-)123(+) progenitor population, is supported by extrinsic factors such as the bone marrow niche. Here, we report that when adherent onto fibronectin or osteoblast components, CD34(+)38(-)123(+) progenitors survive through an integrin-dependent activation of glycogen synthase kinase 3ß (GSK3ß) by serine 9-dephosphorylation. Strikingly, GSK3ß-mediated survival was restricted to leukemic progenitors from female patients. GSK3ß inhibition restored sensitivity to etoposide, and impaired the clonogenic capacities of adherent leukemic progenitors from female patients. In leukemic progenitors from female but not male patients, the scaffolding protein RACK1, activated downstream of α(5)ß(1)-integrin engagement, was specifically upregulated and controlled GSK3ß activation through the phosphatase protein phosphatase 2A (PP2A). In a mirrored manner, survival of adherent progenitors (CD34(+)38(-)) from male but not female healthy donors was partially dependent on this pathway. We conclude that the GSK3ß-dependent survival pathway might be sex-specific in normal immature population and flip-flopped upon leukemogenesis. Taken together, our results strengthen GSK3ß as a promising target for leukemic stem cell therapy and reveal gender differences as a new parameter in anti-leukemia therapy.


Subject(s)
Glycogen Synthase Kinase 3/metabolism , Hematopoietic Stem Cells/metabolism , Neoplastic Stem Cells/metabolism , Adult , Aged , Aged, 80 and over , Antigens, CD34/metabolism , Antineoplastic Agents, Phytogenic/pharmacology , Blotting, Western , Cell Adhesion/drug effects , Cell Survival/drug effects , Cells, Cultured , Etoposide/pharmacology , Female , GTP-Binding Proteins/genetics , GTP-Binding Proteins/metabolism , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3/genetics , Glycogen Synthase Kinase 3 beta , Hematopoietic Stem Cells/pathology , Humans , Indoles/pharmacology , Interleukin-3 Receptor alpha Subunit/metabolism , Leukemia/genetics , Leukemia/metabolism , Leukemia/pathology , Male , Maleimides/pharmacology , Middle Aged , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplastic Stem Cells/pathology , Protein Phosphatase 2/metabolism , RNA Interference , Receptors for Activated C Kinase , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Sex Factors , Tumor Cells, Cultured , Young Adult
16.
J Pediatr Urol ; 7(6): 585-91, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22030455

ABSTRACT

PURPOSE: Mastermind-like domain containing 1 (MAMLD1) is a causative gene for the fetal development of male external genitalia. Almost 10% of patients with both severe and non-severe hypospadias exhibit mutations of MAMLD1. The aim of this work was to determine whether polymorphisms of MAMLD1 are a genetic risk factor for hypospadias. MATERIAL AND METHODS: This study included 150 hypospadias with a range of severities and 150 controls. Direct sequencing of the MAMLD1 coding exons and their flanking splice sites was performed. In silico secondary and tertiary structure prediction and accessibility of changed amino acids were evaluated using JPred, Netsurf and PHYRE software. Functional studies of the transactivation of haplotypes on Hes3 promoter were performed in vitro using cDNAs of missense variants of MAMLD1. RESULTS: The p.P286S polymorphism was identified in 17/150 patients and 12/150 controls (11.3% vs. 8.0%, p = 0.32). The p.N589S polymorphism was identified in 22/150 patients and 12/150 controls (14.6% vs. 8.0%, p = 0.068). The double polymorphism (S-S haplotype) was present in 16/150 patients and 6/150 controls (10.6% vs. 4.0%, p = 0.044, OR = 2.87, CI from 1.09 to 7.55). The association of polymorphisms consistently revealed a modification in the structure prediction or amino acid accessibility in all three in silico models. The P286S, N589S and P286S + N589S proteins did not exhibit reduced transactivating activity on Hes3 promoter. CONCLUSION: Polymorphisms of MAMLD1 gene are frequent in patients with hypospadias. Although no change in transactivation was noted on Hes3 promoter, the in silico studies and the significantly increased incidence of the S-S haplotype in hypospadiac patients raise the hypothesis of a particular susceptibility conferred by these variants.


Subject(s)
DNA-Binding Proteins/genetics , Hypospadias/genetics , Nuclear Proteins/genetics , Polymorphism, Genetic , Transcription Factors/genetics , Child , Child, Preschool , Genetic Predisposition to Disease , Genitalia, Male/abnormalities , Genitalia, Male/embryology , Haplotypes , Humans , Infant , Infant, Newborn , Male , Sequence Analysis, DNA , Transcriptional Activation
18.
Int J Androl ; 34(6 Pt 2): e518-25, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21535007

ABSTRACT

Micropenis is defined as a stretched penile length of less than 2-2.5SD for age. Aetiologies include hypogonadotropic hypogonadism, testicular dysgenesis, defects in testosterone synthesis, androgen resistance [5α-reductase (5αR) deficiency or partial androgen insensitivity] and other rare causes like growth hormone GH deficiency. Often, the cause remains unknown. The aim of this study was to determine whether isolated micropenis with normal plasma testosterone could hide a molecular defect in the androgen pathway. Twenty-six boys with isolated micropenis were included in this study. All of them had 46,XY karyotype, normal luteinizing hormone and follicle-stimulating hormone and a normal plasma testosterone response to human chorionic gonadotropin testing. Androgen receptor (AR), 5αR and steroidogenic factor 1 (SF1) genes were sequenced. A mutation in the AR gene was found in two patients, and a new mutation in the SF1 gene was found in one patient who was the only one to have a low level of inhibin B (InhB). This is the first report of isolated micropenis as a revealing symptom of AR and SF1 mutations. Anti-Mullerian hormone and InhB should thus be evaluated in patients with isolated micropenis, even when plasma testosterone is in the normal range. Detection of gene mutations is helpful for diagnosis, treatment and genetic counselling for probands.


Subject(s)
Genital Diseases, Male/genetics , Amino Acid Sequence , Child , Child, Preschool , Follicle Stimulating Hormone/blood , Humans , Karyotyping , Luteinizing Hormone/blood , Male , Molecular Sequence Data , Mutation , Penis/abnormalities , Sequence Homology, Amino Acid , Steroidogenic Factor 1/chemistry , Steroidogenic Factor 1/genetics , Testosterone/blood
19.
Osteoporos Int ; 22(12): 3055-66, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21359671

ABSTRACT

UNLABELLED: Peripubertal artistic gymnasts display elevated areal bone mineral density at various bone sites, despite delayed menarche and a high frequency of menstrual disorders, factors that may compromise bone health. The concomitant improvement in femoral bone geometry and strength suggested that this type of physical activity might have favourable clinical impact. INTRODUCTION: The purpose of this study is to evaluate the effect of artistic gymnastics (GYM) on areal bone mineral density (aBMD), femoral bone geometry and bone markers and its relationship with the osteoprotegerin (OPG)/rank-ligand (RANKL) system in peripubertal girls. METHODS: Forty-six girls (age 10-17.2 years) were recruited for this study: 23 elite athletes in the GYM group (training 12-30 h/week, age at start of training 5.3 years) and 23 age-matched (± 6 months; leisure physical activity ≤ 3 h/week) controls (CON). The aBMD at whole body, total proximal femur, lumbar spine, mid-radius and skull was determined using dual-X-ray absorptiometry. Hip structural analysis (HSA software) was applied at the femur to evaluate cross-sectional area (CSA, cm(2)), cross-sectional moment of inertia (CSMI, cm(4)), and the section modulus (Z, cm(3)) and buckling ratio at neck, intertrochanteric region and shaft. Markers of bone turnover and OPG/RANKL levels were also analysed. RESULTS: GYM had higher (5.5-16.4%) non-adjusted aBMD and adjusted aBMD for age, fat-free soft tissue and fat mass at all bone sites, skull excepted and the difference increased with age. In the three femoral regions adjusted for body weight and height, CSA (12.5-18%), CSMI (14-18%), Z (15.5-18.6%) and mean cortical thickness (13.6-21%) were higher in GYM than CON, while the buckling ratio (21-27.1%) was lower. Bone markers decreased with age in both groups and GYM presented higher values than CON only in the postmenarchal period. A similar increase in RANKL with age without OPG variation was observed for both groups. CONCLUSION: GYM is associated not only with an increase in aBMD but also an improvement in bone geometry associated with an increase in bone remodelling. These adaptations seem to be independent of the OPG/RANKL system.


Subject(s)
Bone Density/physiology , Femur/anatomy & histology , Gymnastics/physiology , Osteoprotegerin/metabolism , RANK Ligand/metabolism , Absorptiometry, Photon , Adolescent , Bone Remodeling/physiology , Child , Cross-Sectional Studies , Female , Femur/diagnostic imaging , Humans , Lumbar Vertebrae/diagnostic imaging , Osteoprotegerin/blood , RANK Ligand/blood , Radius/diagnostic imaging
20.
J Sports Med Phys Fitness ; 51(1): 160-8, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21297576

ABSTRACT

AIM: Investigated the relationship between leptin levels or bone remodelling and physical fitness level in healthy elderly participants. METHODS: Twenty women and 18 men (mean age 72.7 years, range 59-90) performed a maximal incremental exercise test to evaluate their maximal oxygen uptake (VOmax). Basal blood concentrations of bone biochemical markers (BM) and leptin were analysed. RESULTS: Women presented higher values of leptin than men (+34.7%, P=0.024), but no difference related to gender was observed for the other biological parameters. Leptin levels were positively correlated with Body Mass Index (BMI) in both genders. Whether adjusted or not for BMI, leptin was negatively correlated with VOmax only in men (r=-0.55, P=0.02 and r=-0.57, P=0.01, respectively). No relationship between VOmax or leptin and BM was observed, except for leptin and osteocalcin in men (r=-0.66, P=0.015). CONCLUSION: Our data suggest that neither physical fitness nor leptin level seems to have a noticeable effect in the regulation of bone cell activity in healthy elderly participants. In this specific population, physical fitness plays a crucial role on leptin secretion, independently of BMI variation, and this action appears to be sex-dependent.


Subject(s)
Bone Remodeling/physiology , Bone and Bones/metabolism , Leptin/blood , Physical Fitness/physiology , Aged , Aged, 80 and over , Body Mass Index , Female , Humans , Male , Middle Aged , Osteocalcin/blood , Oxygen Consumption/physiology , Sex Factors
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