Intronic regions of the human coagulation factor VIII gene harboring transcription factor binding sites with a strong bias towards the short-interspersed elements.

Increasing data show that intronic derived regulatory elements, such as transcription factor binding sites (TFBs), play key roles in gene regulation, and malfunction. Accordingly, characterizing the sequence context of the intronic regions of the human coagulation factor VIII (hFVIII) gene can be important. In this study, the intronic regions of the hFVIII gene were scrutinized based on in-silico methods. The results disclosed that these regions harbor a rich array of functional elements such as repetitive elements (REs), splicing sites, and transcription factor binding sites (TFBs). Among these elements, TFBs and REs showed a significant distribution and correlation to each other. This survey indicated that 31% of TFBs are localized in the intronic regions of the gene. Moreover, TFBs indicate a strong bias in the regions far from splice sites of introns with mapping to different REs. Accordingly, TFBs showed highly bias toward Short Interspersed Elements (SINEs), which in turn they covering about 12% of the total of REs. However, the distribution pattern of TFBs-REs showed different bias in the intronic regions, spatially into the Introns 13 and 25. The rich array of SINE-TFBs and CR1-TFBs were situated within 5'UTR of the gene that may be an important driving force for regulatory innovation of the hFVIII gene. Taken together, these data may lead to revealing intronic regions with the capacity to renewing gene regulatory networks of the hFVIII gene. On the other hand, these correlations might provide the novel idea for a new hypothesis of molecular evolution of the FVIII gene, and treatment of Hemophilia A which should be considered in future studies.

Longer trinucleotide repeats of androgen receptor are associated with higher testosterone and low oxytocin levels in diabetic premature ejaculatory dysfunction patients.

BACKGROUND: Despite its worldwide high occurrence, the obscurity regarding the description, epidemiology and management of premature ejaculation remains provocative. It is well established that male premature ejaculatory dysfunction is an increasing problem due to spontaneous ejaculation across a variety of general and clinical subjects. The main goal of this study was to determine the relationships between trinucleotide repeats of the androgen receptor (AR), sex steroids, and pituitary hormones with sexual function in men with type 2 diabetes mellitus (DM) and reported with acquired premature ejaculation (PE). METHODS: A total of 150 normal and 250 PE + DM subjects were enrolled in this study. Each subject was invited to fill out an elaborative questionnaire to acquire precise selective information regarding BMI, duration of PE + DM, self-reported Intra-Vaginal Ejaculatory Latency Time (IELT), sexual and mental health status by using the premature ejaculation diagnostic tool (PEDT) and Beck Depression Inventory-II (BDI-II). Pearson's correlation analysis was used to analyze the relationship between clinical, hormonal, and genetic variables. Ward's minimum variance cluster analysis and principal component analysis were used for evaluation of dependence between genetic, clinical, and demographic parameters. RESULTS: The patients who have the lowest number of (≤21) (CAG)n repeats have higher serum oxytocin levels (114.2 pg/ml; n = 54, 43.2%) than the controls (69.18 pg/ml; n = 22, 17.6%) and the patients with the highest (≥26) number of (CAG)n repeats (62.9 pg/ml; n = 108, 43.2%).On the other hand, patients who have the highest numbers of (CAG)n repeats (≥26) have higher serum testosterone (6.1 ng/ml; n = 108, 43.2% of cohort) lower prolactin (3.01 ng/ml; n = 108, 43.2% of cohort) levels than the controls and patients with the lowest numbers (≤21) of (CAG)n repeats and their TSH (1.53 mIU/L, P < 0.05) levels are lower than those of controls. In the Pearson correlation model, self-estimated IELT demonstrated significantly negative correlation with both (CAG)n and (GCC)n repeats (r = - 0.16, p = 0.0001; r = - 0.19, p = 0.0001) respectively. These repeats have positive correlation with PEDT (r = 0.28, p = 0.0001: r = 0.24, p = 0.0001, whole model) and inversely correlated with BDI-II (r = - 0.25, p = 0.0001). CONCLUSION: This study indicates that androgen receptor polymorphism modulates the endocrine effect on ejaculatory reflex and depends strongly on its "cofactors". Moreover, our results also confirmed an association between long tri-nucleotide repeats of androgen receptor, sex steroids, pituitary, and thyroid hormones in relation to  acquired premature ejaculatory dysfunction in diabetic patients. However, endocrine regulation of PE reflex is a complex phenomenon that requires further investigation.

CONTEXTE: Malgré une fréquence élevée partout dans le monde de l'éjaculation prématurée (EP), le caractère obscur de sa description, de son épidémiologie et de sa prise en charge reste provocateur. Il est avéré que la dysfonction masculine représentée par l'EP est un problème croissant en raison de l'occurrence de l'éjaculation spontanée dans de nombreux sujets généraux et cliniques. L'objectif principal de la présente étude était de déterminer les relations entre le nombre de répétions de trinucléotides du récepteur aux androgènes (RA), les stéroïdes sexuels et les hormones hypophysaires d'une part, et la fonction sexuelle d'hommes qui présentent un Diabète de type 2 (DT2) et qui rapportent une EP acquise. SUJETS ET MÉTHODES: Un total de 150 sujets normaux et de 250 sujets qui présentaient une EP et un DT2 ont été enrôlés dans cette étude. Il a été demandé à chaque sujet de remplir un questionnaire approprié au recueil sélectif d'informations précises concernant l'indice de masse corporelle, la durée de l'EP+ DT2, le temps de latence éjaculatoire intra vaginal (IELT) auto-rapporté, ainsi que les statuts sexuel et mental sur la base de l'outil diagnostic de l'éjaculation prématurée (PEDT) et de l'inventaire de dépression de Beck-II (BDI-II). Les coefficients de corrélation de Pearson ont été utilisés pour évaluer les relations entre les paramètres génétiques, cliniques et démographiques. L'analyse de variance minimale des groupements de Ward et l'analyse en composante principale ont été utilisées pour évaluer la dépendance entre les paramètres génétiques, clinique et démographiques. RÉSULTATS: Les sujets qui avaient le plus faible nombre (≤21) de répétitions de (CAG)n présentaient des taux sériques plus élevés d'ocytocine (114.2 pg/ml; n = 54, 43.2%) que les témoins (69.18 pg/ml; n = 22, 17.6%) et que les sujets avec le nombre le plus élevé (≥26) de répétitions de (CAG)n (62.9 pg/ml; n = 108, 43.2%).D'un autre côté, les sujets qui présentaient le nombre le plus élevé (≥26) de répétitions de (CAG)n avaient des taux sériques de testostérone plus élevés (6.1ng/ml; n = 108, 43.2% de la cohorte) et de prolactine plus bas (3.01ng/ml; n = 108, 43.2% de la cohorte) que les témoins et que les sujets qui présentaient le nombre le plus bas (≥21) de répétitions de (CAG)n; et leurs taux sériques de TSH était plus bas (1.53 mIU/L; p < 0.05) que ceux des témoins. Dans le modèle de corrélation de Pearson, l'IELT auto-rapporté présentait une corrélation négative avec les répétitions à la fois des triplets (CAG)n (r = -0.16, p = 0.0001) et des triplets (GGC)n (r = -0.19, p = 0.0001). Ces répétitions étaient respectivement corrélées positivement avec PEDT (r = 0.28, p = 0.0001; r = 0.24, p = 0.0001, modèle global) et inversement corrélées avec BDI-II (r = -0.25, p = 0.0001). CONCLUSION: Cette étude montre que le polymorphisme du récepteur aux androgènes module l'effet endocrinien sur le reflexe éjaculatoire et qu'il est étroitement dépendant de ses « cofacteurs ¼. De plus, les présents résultats confirment aussi l'association entre les longues répétions de trinucléotides du récepteur aux androgènes, les stéroïdes sexuels, les hormones pituitaires et thyroïdiennes en relation avec une dysfonction éjaculatoire prématurée acquise chez les patients diabétiques. La régulation endocrine du réflexe de l'EP est toutefois un phénomène complexe qui nécessite de futures investigations.

Tri-nucleotide consortium of androgen receptor is associated with low serum FSH and testosterone in asthenospermic men.

Androgen mediating signaling is implicated in regulating the expression of reproductive related genes. Any deviation in the gene expression might be the ignitable precursor for genomic instability that inflames the genomic rearrangements and a leading cause of cancer. The main goal of this study was to determine the relationships between trinucleotide repeats of androgen receptor (AR), sex steroids, and sexual function in men presenting with reduced sperm motility. We investigated the singleton or combinatorial effects of the length of trinucleotide repeats of AR on reproductive hormones, clinical parameters, semen analyses, as well as sexual assessment function of 210 asthenospermic outpatients along with 125 normal subjects. Sexual assessment was executed using the International Index of Erectile Function (IIEF-15 score) which measures erectile function (EF), orgasmic function (OR), sexual desire (SD), intercourse satisfaction (IS), and overall satisfaction. Our findings suggest that long (>26 CAG)n repeats have an inverse correlation with circulatory FSH and T, whereas long (>25 GGC)n repeats have moderated affiliation with reduced sperm concentration. The study revealed a novel finding by exploring the negative correlation between elongated (CAG)n repeats and the cumulative IIEF-15 score, orgasm function (OR), and erectile function (EF) in asthenospermic men. This study examines the tri-nucleotide correlation with sexual function in Punjabi men enhancing our understanding of the regulatory mechanisms of sexual performance. ABBREVIATIONS: AR: androgen receptor; IIEF-15 score: International Index of Erectile Function; EF: erectile function; OR: orgasmic function; SD: sexual desire; IS: intercourse satisfaction; FSH: follicular stimulating hormone; T: testosterone; NTD: N-terminal transactivation domain; DBD: DNA-binding domain; LBD: ligand binding domain; TNR: tri-nucleotide repeat.

Genetic perspective of uniparental mitochondrial DNA landscape on the Punjabi population, Pakistan.

To investigate the uniparental genetic structure of the Punjabi population from mtDNA aspect and to set up an appropriate mtDNA forensic database, we studied maternally unrelated Punjabi (N = 100) subjects from two caste groups (i.e. Arain and Gujar) belonging to territory of Punjab. The complete control region was elucidated by Sanger sequencing and the subsequent 58 different haplotypes were designated into appropriate haplogroups according to the most recently updated mtDNA phylogeny. We found a homogenous dispersal of Eurasian haplogroup uniformity among the Punjab Province and exhibited a strong connotation with the European populations. Punjabi castes are primarily a composite of substantial South Asian, East Asian and West Eurasian lineages. Moreover, for the first time we have defined the newly sub-haplogroup M52b1 characterized by 16223 T, 16275 G and 16438 A in Gujar caste. The vast array of mtDNA variants displayed in this study suggested that the haplogroup composition radiates signals of extensive genetic conglomeration, population admixture and demographic expansion that was equipped with diverse origin, whereas matrilineal gene pool was phylogeographically homogenous across the Punjab. This context was further fully acquainted with the facts supported by PCA scatterplot that Punjabi population clustered with South Asian populations. Finally, the high power of discrimination (0.8819) and low random match probability (0.0085%) proposed a worthy contribution of mtDNA control region dataset as a forensic database that considered a gold standard of today to get deeper insight into the genetic ancestry of contemporary matrilineal phylogeny.

Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family.

BACKGROUND: Intellectual disability (ID) is a neurodevelopmental disorder affecting 1%-3% of the population worldwide. It is characterised by high phenotypic and genetic heterogeneity and in most cases the underlying cause of the disorder is unknown. In our study we investigated a large consanguineous family from Baluchistan, Pakistan, comprising seven affected individuals with a severe form of autosomal recessive ID (ARID) and epilepsy, to elucidate a putative genetic cause. METHODS AND RESULTS: Whole exome sequencing (WES) of a trio, including a child with ID and epilepsy and its healthy parents that were part of this large family, revealed a homozygous missense variant p.R53Q in the lectin mannose-binding 2-like (LMAN2L) gene. This homozygous variant was co-segregating in the family with the phenotype of severe ID and infantile epilepsy; unaffected family members were heterozygous variant carriers. The variant was predicted to be pathogenic by five different in silico programmes and further three-dimensional structure modelling of the protein suggests that variant p.R53Q may impair protein-protein interaction. LMAN2L (OMIM: 609552) encodes for the lectin, mannose-binding 2-like protein which is a cargo receptor in the endoplasmic reticulum important for glycoprotein transport. Genome-wide association studies have identified an association of LMAN2L to different neuropsychiatric disorders. CONCLUSION: This is the first report linking LMAN2L to a phenotype of severe ARID and seizures, indicating that the deleterious homozygous p.R53Q variant very likely causes the disorder.

Molecular Distribution of Deafness Loci in Various Ethnic Groups of the Punjab, Pakistan.

OBJECTIVE: To determine the existence of autosomal recessive deafness loci in different ethnic tribes of the Punjab. STUDY DESIGN: Descriptive observational study. PLACE AND DURATION OF STUDY: Department of Human Genetics and Centre of Excellence in Molecular Biology, University of Health Sciences, Lahore, from July 2009 to March 2012. METHODOLOGY: Healthy willing subjects with autosomal recessive deafness loci were studied for selected deafness loci. Those who were unhealthy and gave history of infectious disease were excluded. DNAextraction was carried out using the inorganic method. Fluorescently labeled microsatellite markers were used for amplification of desired regions by PCR (Polymerase Chain Reaction). Automated allele assignment was performed using the ABI PRISM GeneScan Analysis Software Version 3.7 for Windows NTPlatform. Two-point LOD scores were calculated using the FASTLINK computer package (Schaffer 1996) and MLINK was used for calculation and 95% CI (confidence intervals) were calculated. RESULTS: One hundred and thirty two individuals of 8 families were analyzed. Three families (SAPun-03, SAPun-10 and SAPun-15) were found linked to DFNB12; two families (SAPun-05 and SAPun-17) were found linked to DFNB8/10, while three families (SAPun-06, SAPun-13 and SAPun-19) were found linked to DFNB29, DFNB36 and DFNB37 respectively. CONCLUSION: The genotyping results revealed that DFNB12 locus was the most common followed by DFNB8/10 locus, while the Loci DFNB29, DFNB36 and DFNB37 were less common.