[Show abstract][Hide abstract] ABSTRACT: The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories.
The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference.
Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories.
Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.
Journal of Medical Genetics 04/2014; · 5.70 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: The role of cholesterol in female reproductive physiology has been suspected for a long time, while the molecular bases were unknown. Cholesterol is the precursor of ovarian steroids biosynthesis and is also essential for fertility. In the uterus, cholesterol is essential to achieve correct contractions at term, but an excessive uterine cholesterol concentration has been associated with contractility defects. Liver X Receptor (LXR) alpha and LXR beta are nuclear receptors activated by oxysterols, oxidized derivatives of cholesterol. Since their discovery, the role of LXRs in the control of cholesterol homeostasis has been widely described. Beyond their cholesterol-lowering role, more recent data have linked these nuclear receptors to various physiological processes. In particular, they control ovarian endocrine and exocrine functions, as well as uterine contractility. Their contribution to female reproductive cancers will also be discussed. This review will try to enlighten on the LXRs as a molecular link between dietary cholesterol and reproductive diseases in women. In the future, a better comprehension of the various physiological processes regulated by the LXRs will help to develop new ligands to prevent or to cure these pathologies in women.
Journal of endocrinological investigation 11/2012; · 1.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nutritional status is known to control female reproductive physiology. Many reproductive pathologies such as anorexia nervosa, dystocia and preeclampsia, have been linked to body mass index and to metabolic syndrome. Lipid metabolism has also been associated with ovarian, uterine and placental functions. Among the regulators of lipid homeostasis, the Liver X Receptors (LXRs) and the Liver Receptor Homolog-1 (LRH-1), two members of the nuclear receptor superfamily, play a central role. LXRs are sensitive to intracellular cholesterol concentration and decrease plasma cholesterol, allowing to considering them as "cholesterol sensors". LRH-1 shares many target-genes with LXRs and has been considered for a long time as a real orphan nuclear receptor, but recent findings showed that phospholipids are ligands for this nuclear receptor. Acting in concert, LXRs and LRH-1 could thus be sensitive to slight modifications in cellular lipid balance, tightly maintaining their cellular concentrations. These last years, the use of transgenic mice clarified the roles of these nuclear receptors in many physiological functions. This review will be focused on the roles of LXRs and LRH-1 on female reproduction. Their contribution to ovarian endocrine and exocrine functions, as well as uterine and placental physiology will be discussed. The future challenge will thus be to target these nuclear receptors to prevent lipid-associated reproductive diseases in women.
Molecular and Cellular Endocrinology 06/2012; · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations.
French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations.
In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months).
Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.
[Show abstract][Hide abstract] ABSTRACT: Germline and somatic activating mutations in the LH receptor (LHR) gene have been reported.
Our objective was to perform mutation analysis of the LHR gene of patients with Leydig cell adenoma or hyperplasia. Functional studies were conducted to compare the D578H-LHR mutant with the wild-type (WT)-LHR and the D578G-LHR mutant, a classic cause of testotoxicosis. The three main signal transduction pathways in which LHR is involved were studied.
We describe eight male patients with gonadotropin-independent precocious puberty due to Leydig cell adenoma or hyperplasia.
The D578H-LHR mutation was found in the adenoma or nodule with hyperplasia in all but two patients. D578H-LHR displayed a constitutively increased but noninducible production of cAMP, led to a very high production of inositol phosphates, and induced a slight phosphorylation of p44/42 MAPK in the absence of human chorionic gonadotropin. The D578G-LHR showed a response intermediate between WT-LHR and the D578H-LHR. Subcellular localization studies showed that the WT-LHR was almost exclusively located at the cell membrane, whereas the D578H-LHR showed signs of internalization. D578H-LHR was the only receptor to colocalize with early endosomes in the absence of human chorionic gonadotropin.
Although several LHR mutations have been reported in testotoxicosis, the D578H-LHR mutation, which has been found only as a somatic mutation, appears up until now to be specifically responsible for Leydig cell adenomas. This is reflected by the different activation of the signal transduction pathways, when compared with the WT-LHR or D578G-LHR, which may explain the tumorigenesis in the D578H mutant.
The Journal of clinical endocrinology and metabolism 04/2011; 96(7):E1197-205. · 6.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inherited and acquired changes in pre-mRNA processing have significant roles in human diseases, especially cancer. Characterization of aberrantly spliced mRNAs may thus contribute to understand malignant transformation. We recently reported an anti-oncogenic potential for the SOX9 transcription factor in the colon. For instance, the Sox9 gene knock out in the mouse intestine results in an excess of proliferation with appearance of hyperplasia. SOX9 is expressed in colon cancer cells but its endogenous activity is weak. We looked for SOX9 variants that may impair SOX9 activity in colon cancer cells and we discovered MiniSOX9, a truncated version of SOX9 devoid of transactivation domain as a result of retention of the second intron. A significant overexpression of MiniSOX9 mRNA in human tumor samples compared with their matched normal tissues was observed by real-time reverse transcriptase-PCR. Immunohistochemistry revealed that MiniSOX9 is expressed at high levels in human colon cancer samples whereas it is undetectable in the surrounding healthy tissues. Finally, we discovered that MiniSOX9 behaves as a SOX9 inhibitor, inhibits protein kinase Cα promoter activity and stimulates the canonical Wnt pathway. This potential oncogenic activity of the SOX9 locus gives new insights on its role in colon cancer.
[Show abstract][Hide abstract] ABSTRACT: In 46,XY disorders of sex development, 5α-reductase deficiency is rare and is not usually the first-intention diagnosis in newborn ambiguous genitalia, contrary to partial androgen insensitivity syndrome. Yet the cause of ambiguous genitalia may guide sex assignment, and rapid, precise diagnosis of 5α-reductase deficiency is essential.
The aim of the study was to describe relevant data for clinical diagnosis, biological investigation, and molecular determination from 55 patients with srd5A2 mutations identified in our laboratory over 20 yr to improve early diagnosis.
The study was performed at Montpellier University Hospital.
We studied a cohort of 55 patients with srd5A2 gene mutations.
Genetic analysis of srd5A2 was conducted.
Clitoromegaly (49.1%) and microphallus with various degrees of hypospadias (32.7%) were frequent phenotypes. Female external genitalia (7.3%) and isolated micropenis (3.6%) were rare. Seventy-two percent of patients were initially assigned to female gender; five of them (12.5%) switched to male sex in peripuberty. Over 72% of patients were considered for 5α-reductase deficiency diagnosis when the testosterone/dihydrotestosterone cutoff was 10. In 55 patients (with 20 having a history of consanguinity), we identified 33 different mutations. Five have never been reported: p.G32S, p.Y91H, p.G104E, p.F223S, and c.461delT. Homozygous mutations were present in 69.1% of cases, compound heterozygous mutations in 25.5%, and compound heterozygous mutations alone with the V89L polymorphism in 5.4%. Exons 1 and 4 were most affected, with 35.8 and 21.7% mutant alleles per exon, respectively.
In the largest cohort to date, we demonstrate a wide spectrum of phenotypes and biological profiles in patients with 5α-reductase deficiency, whatever their geographical or ethnic origins.
The Journal of clinical endocrinology and metabolism 02/2011; 96(2):296-307. · 6.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Preeclampsia is a frequent complication of pregnancy and a leading cause of perinatal mortality. Both genetic and environmental risk factors have been identified. Lipid metabolism, particularly cholesterol metabolism, is associated with this disease. Liver X receptors alpha (NR1H3, also known as LXRalpha) and beta (NR1H2, also known as LXRbeta) play a key role in lipid metabolism. They belong to the nuclear receptor superfamily and are activated by cholesterol derivatives. They have been implicated in preeclampsia because they modulate trophoblast invasion and regulate the expression of the endoglin (CD105) gene, a marker of preeclampsia. The aim of this study was to investigate associations between the NR1H3 and NR1H2 genes and preeclampsia.
We assessed associations between single nucleotide polymorphisms of NR1H3 (rs2279238 and rs7120118) and NR1H2 (rs35463555 and rs2695121) and the disease in 155 individuals with preeclampsia and 305 controls. Genotypes were determined by high-resolution melting analysis. We then used a logistic regression model to analyze the different alleles and genotypes for those polymorphisms as a function of case/control status.
We found no association between NR1H3 SNPs and the disease, but the NR1H2 polymorphism rs2695121 was found to be strongly associated with preeclampsia (genotype C/C: adjusted odds ratio, 2.05; 95% CI, 1.04-4.05; p = 0.039 and genotype T/C: adjusted odds ratio, 1.85; 95% CI, 1.01-3.42; p = 0.049).
This study provides the first evidence of an association between the NR1H2 gene and preeclampsia, adding to our understanding of the links between cholesterol metabolism and this disease.
BMC Medical Genetics 01/2011; 12:145. · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
Les mutations du gène TARDBP ont été récemment décrites à la fois dans la SLA familiale et sporadique. Si l’effet modulateur des mutations du gène SOD1 sur le phénotype de la SLA, a été clairement démontré, celui des mutations du gène TARDBP n’a pas été encore étudié sur une grande série.
Étudier les relations entre les mutations du gène TARDBP et le phénotype des patients atteints de SLA familiale et sporadique.
Matériel et méthodes
Les caractéristiques cliniques de 28 patients SLA français liés à une mutation du gène TARDBP ont été analysées et comparées à celles de trois autres cohortes de patients SLA : 1) 737 SLA sporadiques ; 2) 323 SLA familiales ; et 3) la population des SLA avec mutation TARDBP de la littérature internationale, soit 108 patients. Cette analyse a été complétée par l’étude phénotypique plus détaillée des 5 mutations TARDBP les plus souvent rapportées.
Il existait dans le groupe TARDBP une prédominance significative du site de début aux membres supérieurs (p = 0,0000007), une tendance à une évolution plus lente et aucune différence concernant l’âge de début. L’étude génotype-phénotype centrée sur les 5 mutations TARDBP les plus fréquentes montrait des variations dans l’âge de début et dans la durée d’évolution selon les mutations.
Le tableau clinique d’une SLA avec mutation TARDBP, se distingue des autres SLA par un début plus fréquent aux membres supérieurs et une évolution plus lente. Certaines mutations sont associées à un profil plus spécifique mais la corrélation génotype-phénotype nécessitera des groupes plus importants pour une analyse plus fine.
Ces différences pourraient aider le clinicien à privilégier l’analyse d’un gène ou d’un autre (SOD1 ou TARDBP) en fonction du phénotype, les mutations SOD1 débutant, elles, plus souvent aux membres inférieurs.
[Show abstract][Hide abstract] ABSTRACT: 5α steroid reductase deficiency (5αSRD) is an autosomal recessive enzymatic deficiency and mutations in the 5α steroid reductase type 2 gene (SRD5A2) result in male pseudohermaphrodism caused by decreased dihydrotestosterone (DHT) synthesis.
To identify the specific mutations of the SRD5A2 gene in Cypriot patients with 5αSRD.
Five unrelated patients with 46,XY karyotype were examined. Four of them were born with ambiguous genitalia and 1 patient, who was raised as girl, presented with primary amenorrhea. The hCG test was informative (elevated testosterone/DHT) of 5αSRD in 3 out of 4 subjects. Sequencing of the SRD5A2 gene was completed for all patients. Genomic DNA was also isolated from a total of 204 healthy unrelated Cypriot subjects. Screening for the IVS1-2A>G mutation was performed by using direct sequencing and restriction enzyme analysis.
The IVS1-2A>G was identified in homozygosity in 3 patients and in a compound heterozygote state in the other 2 patients, in combination with p.P181L and p.R171S in exon 3, respectively. The carrier frequency in the Cypriot population for the IVS1-2A>G mutation was estimated to be 0.98% or 2 in 204.
The same IVS1-2A>G mutation in the SRD5A2 gene seems to characterize all Cypriot patients with 5αSRD diagnosed so far. Furthermore this relatively rare genetic defect, which has only been reported previously in a single case in the Eastern Mediterranean region, is very likely to be the result of a founder effect.
Journal of endocrinological investigation 12/2010; 33(11):810-4. · 1.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical efficacy of chemotherapy in colorectal cancer is subjected to broad inter-individual variations leading to the inability to predict outcome and toxicity. The topoisomerase I inhibitor irinotecan (CPT-11) is worldwide approved for the treatment of metastatic colorectal cancer and undergoes extensive peripheral and tumoral metabolism. PXR is a xenoreceptor activated by many drugs and environmental compounds regulating the expression of drug metabolism and transport genes in detoxification organs such as liver and gastrointestinal tract. Considering the metabolic pathway of irinotecan and the tissue distribution of Pregnane x Receptor (PXR), we hypothesized that PXR could play a key role in colon cancer cell response to irinotecan.
PXR mRNA expression was quantified by RT-quantitative PCR in a panel of 14 colon tumor samples and their matched normal tissues. PXR expression was modulated in human colorectal cancer cells LS174T, SW480 and SW620 by transfection and siRNA strategies. Cellular response to irinotecan and its active metabolic SN38 was assessed by cell viability assays, HPLC metabolic profiles and mRNA quantification of PXR target genes. We showed that PXR was strongly expressed in colon tumor samples and displayed a great variability of expression. Expression of hPXR in human colorectal cancer cells led to a marked chemoresistance to the active metabolite SN38 correlated with PXR expression level. Metabolic profiles of SN38 showed a strong enhancement of SN38 glucuronidation to the inactive SN38G metabolite in PXR-expressing cells, correlated with an increase of UDPglucuronosyl transferases UGT1A1, UGT1A9 and UGT1A10 mRNAs. Inhibition of PXR expression by lentivirus-mediated shRNA, led to SN38 chemoresistance reversion concomitantly to a decrease of UGT1A1 expression and SN38 glucuronidation. Similarly, PXR mRNA expression levels correlated to UGT1A subfamily expression in human colon tumor biopsies.
Our results demonstrate that tumoral metabolism of SN38 is affected by PXR and point to potential therapeutic significance of PXR quantification in the prediction of irinotecan response. Furthermore, our observations are pharmacologically relevant since many patients suffering from cancer diseases are often exposed to co-medications, food additives or herbal supplements able to activate PXR. A substantial part of the variability observed among patients might be caused by such interactions.
Molecular Cancer 03/2010; 9:46. · 5.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pregnane X receptors (PXRs) and the constitutive androstane receptor (CAR) were initially isolated as nuclear receptors regulating xenobiotic metabolism and elimination, alleviating chemical insults. However, recent works suggest that these xenoreceptors play an endobiotic role in modulating hepatic lipid metabolism. In this study, we show that CAR activators]phenobarbital and 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] induce the lipogenic gene thyroid hormone-responsive spot 14 protein (THRSP) (or Spot14, S14) expression in human hepatocytes. In addition, we report that treatment of wild-type mice with mCAR activators (phenobarbital and 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene) efficiently increases thrsp expression, in contrast to CAR null mice. We demonstrate that CAR directly transactivates THRSP promoter through the direct repeat with 4-bp spacer thyroid hormone and PXR response element. Deletion or point mutations within this PXR response element led to a drastic inhibition of CAR-mediated THRSP transactivation. Gel-shift analysis revealed that the CAR/retinoid X receptor complex binds to this element. In conclusion, our results indicate that THRSP gene is a CAR and PXR target gene. Because THRSP expression correlates with lipogenesis and insulin sensitivity, our data suggest that CAR and/or PXR activating drugs and xenobiotics may promote aberrant hepatic de novo lipogenesis leading potentially to fatty liver diseases and insulin resistance.
[Show abstract][Hide abstract] ABSTRACT: Gemcitabine (2',2'-difluorodeoxycytidine) is a major antimetabolite cytotoxic drug with a wide spectrum of activity against solid tumors. Hepatic elimination of gemcitabine depends on a catabolic pathway through a deamination step driven by the enzyme cytidine deaminase (CDA). Severe hematologic toxicity to gemcitabine was reported in patients harboring genetic polymorphisms in CDA gene. High-resolution melting (HRM) analysis of polymerase chain reaction amplicon emerges today as a powerful technique for both genotyping and gene scanning strategies. In this study, 46 DNA samples from gemcitabine-treated patients were subjected to HRM analysis on a LightCycler 480 platform. Residual serum CDA activity was assayed as a surrogate marker for the overall functionality of this enzyme. Genotyping of three well-described single nucleotide polymorphisms in coding region (c.79A>C, c.208G>A and c.435C>T) was successfully achieved by HRM analysis of small polymerase chain reaction fragments, whereas unknown single nucleotide polymorphisms were searched by a gene scanning strategy with longer amplicons (up to 622 bp). The gene scanning strategy allowed us to find a new intronic mutation c.246+37G>A in a female patient displaying marked CDA deficiency and who had an extreme toxic reaction with a fatal outcome to gemcitabine treatment. Our work demonstrates that HRM-based methods, owing to their simplicity, reliability, and speed, are useful tools for diagnosis of CDA deficiency and could be of interest for personalized medicine.
Therapeutic drug monitoring 12/2009; 32(1):53-60. · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is no longer adequate to choose reference genes blindly. We present the first study that defines the suitability of 12 reference genes commonly used in cancer studies (ACT, ALAS, B2M, GAPDH, HMBS, HPRT, KALPHA, RPS18, RPL27, RPS29, SHAD and TBP) for the normalization of quantitative expression data in the field of head and neck squamous cell carcinoma (HNSCC).
Raw expression levels were measured by RT-qPCR in HNSCC and normal matched mucosa of 46 patients. We analyzed the expression stability using geNorm and NormFinder and compared the expression levels between subgroups. In HNSCC and/or normal mucosa, the four best normalization genes were ALAS, GAPDH, RPS18 and SHAD and the most stable combination of two genes was GAPDH-SHAD. We recommend using KALPHA-TBP for the study of T1T2 tumors, RPL27-SHAD for T3T4 tumors, KALPHA-SHAD for N0 tumors, and ALAS-TBP for N+ tumors. ACT, B2M, GAPDH, HMBS, HPRT, KALPHA, RPS18, RPS29, SHAD and TBP were slightly misregulated (<1.7-fold) between tumor and normal mucosa but can be used for normalization, depending on the resolution required for the assay.
In the field of HNSCC, this study will guide researchers in selecting the most appropriate reference genes from among 12 potentially suitable reference genes, depending on the specific setting of their experiments.
[Show abstract][Hide abstract] ABSTRACT: Analysis of 23 published transcriptome studies allowed us to identify nine genes displaying frequent alterations in HNSCC (FN1, MMP1, PLAU, SPARC, IL1RN, KRT4, KRT13, MAL, and TGM3). We aimed to independently confirm these dysregulations and to identify potential relationships with clinical data for diagnostic, staging and prognostic purposes either at the tissue level or in saliva rinse.
For a period of two years, we systematically collected tumor tissue, normal matched mucosa and saliva of patients diagnosed with primary untreated HNSCC. Expression levels of the nine genes of interest were measured by RT-qPCR in tumor and healthy matched mucosa from 46 patients. MMP1 expression level was measured by RT-qPCR in the salivary rinse of 51 HNSCC patients and 18 control cases.
Dysregulation of the nine genes was confirmed by the Wilcoxon test. IL1RN, MAL and MMP1 were the most efficient diagnostic markers of HNSCC, with ROC AUC > 0.95 and both sensitivity and specificity above 91%. No clinically relevant correlation was found between gene expression level in tumor and T stage, N stage, tumor grade, global survival or disease-free survival. Our preliminary results suggests that with 100% specificity, MMP1 detection in saliva rinse is potentially useful for non invasive diagnosis of HNSCC of the oral cavity or oropharynx, but technical improvement is needed since sensitivity was only 20%.
IL1RN, MAL and MMP1 are prospective tumor diagnostic markers for HNSCC. MMP1 overexpression is the most promising marker, and its detection could help identify tumor cells in tissue or saliva.
[Show abstract][Hide abstract] ABSTRACT: Cushing's syndrome (CS) may develop at any time in childhood. In the neonatal period, the major cause is the overactivation of adrenal cells within the context of McCune-Albright syndrome (MAS). The hypercorticism usually appears with other clinical signs of MAS. We report here a case of isolated neonatal CS as the initial evidence of MAS. This newborn girl was referred to our pediatric endocrine unit at the age of 3 months for hypotonia and growth retardation. Clinical examination revealed facial plethora, moon face, and swollen limbs. Laboratory data demonstrated ACTH-independent CS. Magnetic resonance imaging showed moderate bilateral adrenal hyperplasia, though more marked in the left adrenal gland, without nodules. This peripheral hypercorticism without well-defined adrenal tumor was suggestive of MAS, although no other signs like precocious puberty or café-au-lait spots were found. An activating Gsalpha gene mutation was found on DNA extracted from blood. Because MAS is a somatic disease, usually with unilateral effects, we tried to remove only the larger adrenal gland, where the mutation was demonstrated. This female newborn later developed the classical triad of MAS, reinforcing this diagnosis. Cushing's syndrome in infants, even when isolated, may suggest a diagnosis of MAS.
Hormone Research 01/2009; 72(5):315-9. · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inactivating LH receptor (LHR) mutations have been described so far in men as well as in women. Phenotypes in men have been variable with in nearly all cases impairment of sex differentiation or azoospermia. We report a milder reproductive phenotype both in a male patient and his sister.
We describe a family that carries a homozygous mutation G-->A at position -1 at the intron 10-exon 11 boundary of the LHR gene. The male patient presented with delayed puberty, micropenis and oligospermia. Two of his sisters were homozygous for the same mutation and were infertile. Surprisingly, one of them was found to have had regular ovarian cycles for years and showed normal LH values (6.5 and 10.6 mIU/ml for LH and FSH, respectively). In vitro analysis showed that this altered splicing resulted in an LHR from which eight amino acids are deleted from the extracellular domain (Delta Tyr(317)-Ser(324)). In vitro expression has shown that the receptor was expressed and capable of LH-induced signaling, albeit with reduced potency (P < 0.001).
LHR mutations may represent an underestimated cause of infertility in women, in addition to being responsible for male hypogonadism with reduced spermatogenesis.
Human Reproduction 09/2008; 23(8):1917-23. · 4.67 Impact Factor