Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations.
Ontology highlight
ABSTRACT:
SUBMITTER: Prado MJ
PROVIDER: S-EPMC8745212 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundAntithrombin (AT) is the main physiological anticoagulant involved in hemostasis. Hereditary AT deficiency is a rare autosomal dominant thrombotic disease mainly caused by mutations in SERPINC1, which was usually manifested as venous thrombosis and pulmonary embolism. In this study, we analyzed the clinical characteristics and screened for mutant genes in two pedigrees with hereditary AT deficiency, and the functional effects of the pathogenic mutations were evaluated.MethodsCandidate gene variants were analyzed by next-generation sequencing to screen pathogenic mutations in probands, followed by segregation analysis in families by Sanger sequencing. Mutant and wild-type plasmids were constructed and transfected into HEK293T cells to observe protein expression and cellular localization of SERPINC1. The structure and function of the mutations were analyzed by bioinformatic analyses.ResultsThe proband of pedigree A with AT deficiency carried a heterozygous frameshift mutation c.1377delC (p.Asn460Thrfs*20) in SERPINC1 (NM000488.3), a 1377C base deletion in exon 7 resulting in a backward shift of the open reading frame, with termination after translation of 20 residues, and a different residue sequence translated after the frameshift. Bioinformatics analysis suggests that the missing amino acid sequence caused by the frameshift mutation might disrupt the disulfide bond between Cys279 and Cys462 and affect the structural function of the protein. This newly discovered variant is not currently included in the ClinVar and HGMD databases. p.Arg229* resulted in a premature stop codon in exon 4, and bioinformatics analysis suggests that the truncated protein structure lost its domain of interaction with factor IX (Ala414 site) after the deletion of nonsense mutations. However, considering the AT truncation protein resulting from the p.Arg229* variant loss a great proportion of the molecule, we speculate the variant may affect two functional domains HBS and RCL and lack of the corresponding function. The thrombophilia and decreased-AT-activity phenotypes of the two pedigrees were separated from their genetic variants. After lentiviral plasmid transfection into HEK293T cells, the expression level of AT protein decreased in the constructed c.1377delC mutant cells compared to that in the wild-type, which was not only reduced in c.685C > T mutant cells but also showed a significant band at 35 kDa, suggesting a truncated protein. Immunofluorescence localization showed no significant differences in protein localization before and after the mutation.ConclusionsThe p.Asn460Thrfs*20 and p.Arg229* variants of SERPINC1 were responsible for the two hereditary AT deficiency pedigrees, which led to AT deficiency by different mechanisms. The p.Asn460Thrfs*20 variant is reported for the first time.
| S-EPMC9830717 | biostudies-literature
Project description:Dominant-negative growth hormone gene (GH1) mutations cause familial isolated growth hormone deficiency type II (IGHD II), which is characterized by GH deficiency, occasional multiple anterior pituitary hormone deficiencies, and anterior pituitary hypoplasia. We have previously shown that 17.5-/22-kDa GH1 transcript ratios correlate with the severity of the IGHD II phenotype. We hypothesized that different pharmaceutical agents could affect the GH1 transcript ratio by modulating alternative splicing.We exposed peripheral blood mononuclear cells from IGHD II patients and unaffected family members to different pharmacologic agents and then determined the 17.5-/22-kDa transcript ratios by real-time PCR.Dexamethasone and digoxin significantly increased the 17.5-/22-kDa transcript ratio, while sodium butyrate and 5-iodotubericidin significantly decreased the ratio.Since we have previously shown that the ratio of the 17.5-/22-kDa GH1 transcripts correlates with severity of the IGHD II phenotype, our findings here suggest that selected previously unconsidered agents could possibly reduce the severity of IGHD II, while other agents could possibly exacerbate the disease phenotype.
| S-EPMC5439858 | biostudies-other
Project description:BackgroundSteroid 21-hydroxylase deficiency is present in 90-95% of all cases with congenital adrenal hyperplasia (CAH), an autosomal recessive disorder. It can present as the severe classical salt wasting (SW) or simple virilising (SV) form, or the milder, nonclassical form. Nine pseudogene-derived point mutations account for about 80% of all defects in the CYP21A2 gene coding the 21-hydroxylase enzyme.MethodsWe have studied nine CYP21A2 point mutations in 61 Macedonian and 24 Serbian patients with different clinical presentations of CAH, using the PCR/ACRS method.ResultsSix different mutations were detected in 71.3% of alleles of the Macedonian patients. The most prevalent mutation was IVS2. Mutations were detected in 85.4% of the SW, 83.4% SV and 47.7% LO alleles. In the Macedonian patients the most common genotype was IVS2/IVS2. Five different mutations were detected in 64.6% of alleles of the Serbian patients. The most prevalent was P30L. Mutations were present in 83.3% SW, 80% SV and 50% of the LO alleles. In the Serbian patients, the P30L/P30L genotype was the most frequent.ConclusionsSpecific CYP21A2 mutations are involved in different clinical forms of CAH. High frequency of P30L was found in both populations. Also, high prevalence of the mild P30L mutation was found in both the Macedonian and Serbian classical SV patients. Our findings support the role of the P30L mutation in pronounced virilisation. An unusual finding is the low frequency of V281L in the Macedonian non-classical patients and its absence in the ones from Serbia.
| S-EPMC4922339 | biostudies-literature
Project description:In Portugal, heterozygous loss-of-function mutations in the progranulin (GRN) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). GRN mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the GRN mutation spectrum, investigated in 257 FTD patients and 19 family members from the central/north region of Portugal using sequencing methods. Seven different pathogenic variants were identified in 46 subjects including 40 patients (16%) and 6 relatives (32%). bvFTD was the most common clinical presentation among the GRN mutation patients, who showed a global pattern of moderate-to-severe frontotemporoparietal deficits in the neuropsychological evaluation. Interestingly, two mutations were novel (p.Thr238Profs*18, p.Leu354Profs*16), and five were previously described, although three of them only in the Portuguese population, suggesting a population-specific GRN mutational spectrum. The subjects harboring a GRN mutation showed a significant reduction in serum PGRN levels, supporting the pathogenic nature of these variants. This work broadens the mutation spectrum of GRN and the identification of the underlying GRN mutations provided an accurate genetic counselling and allowed the enrolment of subjects with GRN mutations (both asymptomatic and symptomatic) in ongoing clinical trials, which is essential to test new drugs for the disease.
| S-EPMC10778719 | biostudies-literature
Project description:Many studies have shown that, while reading, the brain works a sort of decomposing process of words, reducing them to its morphemes. Moreover, many studies have shown that morphological awareness, which is the ability to reflect upon the structure of words, may contribute to reading in Brazilian Portuguese. The present study investigated morphological priming in children and evaluated the correlation between morphological priming and morphological awareness scores. One hundred and forty-one children took part in this research: 35 second graders, 33 third graders, 33 fourth graders, and 40 fifth graders. They performed a lexical decision task (LDT) and morphological awareness task. Results indicate that as early as the second grade, children show some degree of morphological priming effects. In addition, children from the fifth grade presented morphological priming effects similar to those of a skilled reader. No correlations between morphological awareness scores and morphological priming effects were found.
| S-EPMC6967254 | biostudies-literature
Project description:Phosphoglycerate kinase (PGK) catalyzes an important ATP-generating step in glycolysis. PGK1 deficiency is an uncommon X-linked inherited disorder, generally characterized by various combinations of non-spherocytic hemolytic anemia, neurological dysfunctions, and myopathies. Patients rarely exhibit all three clinical features. To provide a molecular framework to the different pathological manifestations, all known mutations were reviewed and 16 mutant enzymes, obtained as recombinant forms, were functionally and structurally characterized. Most mutations heavily affect thermal stability and to a different extent catalytic efficiency, in line with the remarkably low PGK activity clinically observed in the patients. Mutations grossly impairing protein stability, but moderately affecting kinetic properties (p.I47N, p.L89P, p.C316R, p.S320N, and p.A354P) present the most homogeneous correlation with the clinical phenotype. Patients carrying these mutations display hemolytic anemia and neurological disorders, and,except for p.A354P variant, no myopaty. Variants highly perturbed in both catalytic efficiency (p.G158V, p.D164V, p.K191del, D285V, p.D315N, and p.T378P) and heat stability (all, but p.T378P) result to be mainly associated with myopathy alone. Finally, mutations faintly affecting molecular properties (p.R206P, p.E252A, p.I253T, p.V266M, and p.D268N) correlate with a wide spectrum of clinical symptoms. These are the first studies that correlate the clinical symptoms with the molecular properties of the mutant enzymes. All findings indicate that the different clinical manifestations associated with PGK1 deficiency chiefly depend on the distinctive type of perturbations caused by mutations in the PGK1 gene, highlighting the need for determination of the molecular properties of PGK variants to assist in prognosis and genetic counseling. However, the clinical symptoms can not be understood only on the bases of molecular properties of the mutant enzyme. Different (environmental, metabolic, genetic and/or epigenetic) intervening factors can contribute toward the expression of PGK deficient clinical phenotypes.
| S-EPMC3279470 | biostudies-literature
Project description:BackgroundBiotinidase deficiency (OMIM 253260) is an autosomal recessively inherited disorder affecting about 1/60,000 people worldwide. The absence or deficiency of biotinidase impairs free biotin recycling and affects biotin-dependent carboxylase functions.MethodsA Chinese patient with spontaneous recurrent epilepsy, an eczema-like rash, hair loss, hypotonia, and hearing loss began at three months of age. Her biotinidase activity was 1.0 nmol/ml/min, 9.5% of the mean control activity, which confirmed profound biotinidase deficiency.ResultsCompound heterozygous for c.250-1G > C and c.878dupT variants in the BTD gene were identified in this patient. These two variants were novel and absent in the population matched controls and any databases.ConclusionsThis study expanded the mutation spectrum of alterations of the BTD gene. Our patient also emphasized the critical role of biotinidase activity measurement combined with mutation analysis in early diagnosis of biotinidase deficiency.
| S-EPMC8077094 | biostudies-literature
Project description:In this article, we present the Brazilian Portuguese Lexicon, a new word-based corpus for psycholinguistic and computational linguistic research in Brazilian Portuguese. We describe the corpus development, the specific characteristics on the internet site and database for user access. We also perform distributional analyses of the corpus and comparisons to other current databases. Our main objective was to provide a large, reliable, and useful word-based corpus with a dynamic, easy-to-use, and intuitive interface with free internet access for word and word-criteria searches. We used the Núcleo Interinstitucional de Linguística Computacional's corpus as the basic data source and developed the Brazilian Portuguese Lexicon by deriving and adding metalinguistic and psycholinguistic information about Brazilian Portuguese words. We obtained a final corpus with more than 30 million word tokens, 215 thousand word types and 25 categories of information about each word. This corpus was made available on the internet via a free-access site with two search engines: a simple search and a complex search. The simple engine basically searches for a list of words, while the complex engine accepts all types of criteria in the corpus categories. The output result presents all entries found in the corpus with the criteria specified in the input search and can be downloaded as a.csv file. We created a module in the results that delivers basic statistics about each search. The Brazilian Portuguese Lexicon also provides a pseudoword engine and specific tools for linguistic and statistical analysis. Therefore, the Brazilian Portuguese Lexicon is a convenient instrument for stimulus search, selection, control, and manipulation in psycholinguistic experiments, as also it is a powerful database for computational linguistics research and language modeling related to lexicon distribution, functioning, and behavior.
| S-EPMC4668042 | biostudies-literature
Project description:Background21-Hydroxylase deficiency (21-OHD) caused by the CYP21A2 gene mutations is the most common form of congenital adrenal hyperplasia. It is an autosomal recessive disorder that results in defective synthesis of cortisol and aldosterone. The incidences of various CYP21A2 gene mutations and the genotype-phenotype correlations vary among different populations.Materials and methodsThe clinical and molecular data of 22 patients were analyzed in this study. All patients were recruited from the neonatal intensive care unit. Locus-specific polymerase chain reaction and Sanger sequencing were applied to identify gene micro-conversions, and multiplex ligation-dependent probe amplification was used to detect large fragment deletions/conversions. Then, the genotypes were categorized in to Null, A, B, C, and D groups to analyze the relationships between genotypes and phenotypes.ResultsAll 22 patients were classified into classic salt wasting form of 21-OHD. Molecular defects were detected in 44 alleles (100%). Micro-conversion mutation IVS2-13A/C>G (70.5%) is most common in our cohort, followed by large gene deletions and conversions (22.7%). The other mutations present were p.R357 W (4.5%) and E6 Cluster (2.3%). Genotypes of 22 patients (100%) were consistent with the predictive phenotypes.ConclusionIn this study, we identified the mutation spectrum of CYP21A2 gene in Chinese patients, especially the younger age cohort in pediatrics. Micro-conversions were the most popular mutations. Moreover, the genotypes and phenotypes were well correlated in this cohort of salt wasting 21-OHD recruited from neonatal intensive care unit.
| S-EPMC7667303 | biostudies-literature
Project description:Colorectal cancer (CRC) is the third most common type of cancer among men and the second among women in Brazil. Despite the high incidence and significance of CRC in Brazil, very little is known about its prevalence among the asymptomatic population. Recently, a CRC screening program was implemented at the Cancer Hospital of Barretos. Characterization of the clinical findings detected in the screening population and the prevalence of basal CRC might contribute to better organization of the program and define the best strategy for a future national screening program. We hypothesize that recruitment and the early outcomes of our screening program based on the fecal immunochemical test (FIT) will differ from the outcomes corresponding to other populations due to sociodemographic differences. Aims: i. To implement a data collection and storage system for follow-up of the screening program participants and to measure early outcomes (adenoma, advanced adenoma and cancer) and associate them with sociodemographic risk factors; ii. to quantify the risk of CRC in the Brazilian population and to develop algorithms for risk stratification of CRC screening; and iii. to compare the risk stratification to other countries with low, medium and high incomes. Methods: Individuals aged 50 to 65 years will be included in the HCB screening program from November 2017 to December 2018. The following data will be collected from all participants: sociodemographic and ethnic (skin color) characteristics; risk factors for CRC, such as smoking and drinking; comorbidities, including diabetes mellitus and arterial hypertension; and FIT, colonoscopy and histopathology examination results. Data collection will be performed using the REDCap data collection/database system. The risk score will be formulated using the Chi-square test (or Fisher’s exact test) and simple logistic regression, and the regression coefficients will be calculated. Then, the model identified for the training sample will be replicated with a validation sample. The resulting score will be used to calculate the sensitivity, specificity, positive predictive value, negative predictive value, accuracy, area under the receiver operating characteristic (ROC) curve and Kolmogorov D statistic.
| 2259905 | ecrin-mdr-crc