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1.
Mol Genet Metab ; 140(4): 107713, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37922835

RESUMO

Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive neurodegenerative disorder with enzyme replacement therapy available. We present two siblings with a clinical diagnosis of CLN2 disease, but no identifiable TPP1 variants after standard clinical testing. Long-read sequencing identified a homozygous deep intronic variant predicted to affect splicing, confirmed by clinical DNA and RNA sequencing. This case demonstrates how traditional laboratory assays can complement emerging molecular technologies to provide a precise molecular diagnosis.


Assuntos
Lipofuscinoses Ceroides Neuronais , Tripeptidil-Peptidase 1 , Humanos , Serina Proteases/genética , Aminopeptidases/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Lipofuscinoses Ceroides Neuronais/genética
2.
J Endocr Soc ; 6(10): bvac127, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36111273

RESUMO

Context: Autosomal dominant and rarely de novo gain-of-function variants in the LHCGR gene are associated with precocious male puberty, while somatic LHCGR variants have been found in isolated Leydig cell adenomas and Leydig cell hyperplasia. Bilateral diffuse Leydig cell tumor formation in peripheral precocious male puberty has not been reported. Case Description: We present a boy with gonadotropin-independent precocious puberty and rapid virilization beginning in infancy resistant to standard therapy. Treatment with abiraterone in addition to letrozole and bicalutamide proved effective. Bilateral diffuse Leydig cell tumors were identified at age 5 years. Results: Whole-genome sequencing of tumor and blood samples was performed. The patient was confirmed to have bilateral, diffuse Leydig cell tumors harboring the somatic, gain-of-function p.Asp578His variant in the LHCGR gene. Digital droplet polymerase chain reaction of the LHCGR variant performed in tumor and blood samples detected low levels of this same variant in the blood. Conclusion: We report a young boy with severe gonadotropin-independent precocious puberty beginning in infancy who developed bilateral diffuse Leydig cell tumors at age 5 years due to a somatic gain-of-function p.Asp578His variant in LHCGR. The gain-of-function nature of the LHCGR variant and the developmental timing of the somatic mutation likely play a role in the risk of tumor formation. Abiraterone (a CYP17A1 inhibitor), in combination with an antiandrogen, aromatase inhibitor, and glucocorticoid, appears to be an effective therapy for severe peripheral precocious puberty in boys.

3.
Genet Med ; 23(8): 1514-1521, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33846581

RESUMO

PURPOSE: Reports have questioned the dogma of exclusive maternal transmission of human mitochondrial DNA (mtDNA), including the recent report of an admixture of two mtDNA haplogroups in individuals from three multigeneration families. This was interpreted as being consistent with biparental transmission of mtDNA in an autosomal dominant-like mode. The authenticity and frequency of these findings are debated. METHODS: We retrospectively analyzed individuals with two mtDNA haplogroups from 2017 to 2019 and selected four families for further study. RESULTS: We identified this phenomenon in 104/27,388 (approximately 1/263) unrelated individuals. Further study revealed (1) a male with two mitochondrial haplogroups transmits only one haplogroup to some of his offspring, consistent with nuclear transmission; (2) the heteroplasmy level of paternally transmitted variants is highest in blood, lower in buccal, and absent in muscle or urine of the same individual, indicating it is inversely correlated with mtDNA content; and (3) paternally transmitted apparent large-scale mtDNA deletions/duplications are not associated with a disease phenotype. CONCLUSION: These findings strongly suggest that the observed mitochondrial haplogroup of paternal origin resulted from coamplification of rare, concatenated nuclear mtDNA segments with genuine mtDNA during testing. Evaluation of additional specimen types can help clarify the clinical significance of the observed results.


Assuntos
DNA Mitocondrial , Mitocôndrias , DNA Mitocondrial/genética , Haplótipos , Humanos , Masculino , Mitocôndrias/genética , Fenótipo , Estudos Retrospectivos
5.
Psychiatry Res Neuroimaging ; 285: 1-8, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30711709

RESUMO

The serotonin transporter (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) gene polymorphisms have been associated with risk for affective disorders and functional variability of the amygdala. We examined whether the two genotypes interactively influence intrinsic functional connectivity (FC) of the amygdala and whether FC mediates the genetic association with anxiety. Eighty genotyped healthy adults underwent resting state fMRI and completed the self-reported State-Trait Anxiety Inventory. Interactive genetic association with anxiety was observed such that effects of 5-HTTLPR depended on the BDNF Val66Met polymorphism (rs6265 variant), with higher anxiety scores in short and Met carriers compared to the other allelic groups. Voxel-wise FC with left and right amygdala seeds identified regions that were sensitive to variability in anxiety scores. A significant moderated mediation model demonstrated that the effect of 5-HTTLPR genotype on anxiety, moderated by BDNF Val66Met genotype, was fully mediated by FC between the left amygdala and the right dorsolateral prefrontal cortex, a cognitive control-related region, during a task-free state. FC was highest in carriers of the 5-HTTLPR short allele and BDNF Met allele. These findings establish intrinsic amygdala-prefrontal functional connectivity as a potential intermediate phenotype for anxiety, an important step toward identification of causal pathways for vulnerability to affective disorders.


Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Ansiedade/diagnóstico por imagem , Ansiedade/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Rede Nervosa/diagnóstico por imagem , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Tonsila do Cerebelo/fisiologia , Epistasia Genética/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Rede Nervosa/fisiologia , Polimorfismo Genético/genética , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiologia , Adulto Jovem
7.
Autism Res ; 12(2): 200-211, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30556326

RESUMO

Amygdala dysfunction has been implicated in numerous neurodevelopmental disorders, including autism spectrum disorder (ASD). Previous studies in mice and humans, respectively, have linked Pac1r/PAC1R function to social behavior and PTSD-susceptibility. Based on this connection to social and emotional processing and the central role played by the amygdala in ASD, we examined a putative role for PAC1R in social deficits in ASD and determined the pattern of gene expression in the developing mouse and human amygdala. We reveal that Pac1r/PAC1R is expressed in both mouse and human amygdala from mid-neurogenesis through early postnatal stages, critical time points when altered brain trajectories are hypothesized to unfold in ASD. We further find that parents of autistic children carrying a previously identified PTSD-risk genotype (CC) report greater reciprocal social deficits compared to those carrying the non-risk GC genotype. Additionally, by exploring resting-state functional connectivity differences in a subsample of the larger behavioral sample, we find higher functional connectivity between the amygdala and right middle temporal gyrus in individuals with the CC risk genotype. Thus, using multimodal approaches, our data reveal that the amygdala-expressed PAC1R gene may be linked to severity of ASD social phenotype and possible alterations in brain connectivity, therefore potentially acting as a modifier of amygdala-related phenotypes. Autism Res 2019, 12: 200-211 © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this multimodal study across mouse and human, we examined expression patterns of Pac1r/PAC1R, a gene implicated in social behavior, and further explored whether a previously identified human PTSD-linked mutation in PAC1R can predict brain connectivity and social deficits in ASD. We find that PAC1R is highly expressed in the both the mouse and human amygdala. Furthermore, our human data suggest that PAC1R genotype is linked to severity of social deficits and functional amygdala connectivity in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Encéfalo/diagnóstico por imagem , Genótipo , Imageamento por Ressonância Magnética/métodos , Fenótipo , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Adolescente , Animais , Transtorno do Espectro Autista/fisiopatologia , Encéfalo/fisiopatologia , Mapeamento Encefálico/métodos , Criança , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Mol Genet Genomic Med ; 6(3): 401-408, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29624921

RESUMO

BACKGROUND: Interleukin-15 (IL-15) is a myokine associated with muscle strength, possibly by attenuating protein breakdown. A variant in the alpha-receptor (IL-15Rα 1775 A>C, rs2228059) partially modulates the muscle strength and size response to resistance training. We examined if this polymorphism associated with habitual physical activity among European-American adults. METHODS: Men (n = 240, 23.7 ± 0.3 year, body mass index [BMI] 25.3 ± 0.3 kg/m2 ) and women (n = 292, 23.2 ± 0.3 year, 24.0 ± 0.3 kg/m2 ) were genotyped. Physical activity phenotypes were derived from the Paffenbarger Physical Activity Questionnaire. Analysis of covariance (ancova) tested log-transformed differences between the IL-15Rα genotype and physical activity phenotypes by gender with age and BMI as covariates. RESULTS: Men with the IL-15Rα 1775AA genotype spent more time in light intensity physical activity (39.4 ± 2.4 hr/week) than men with the CC genotype (28.6 ± 2.3 hr/week, (p = .009). CONCLUSION: Further research is needed to confirm our finding and determine the possible mechanisms by which the IL-15Rα variant modulates light intensity physical activity.


Assuntos
Exercício Físico/fisiologia , Subunidade alfa de Receptor de Interleucina-15/genética , Adulto , Alelos , Composição Corporal , Índice de Massa Corporal , Feminino , Frequência do Gene/genética , Variação Genética/genética , Genótipo , Humanos , Interleucina-15/genética , Subunidade alfa de Receptor de Interleucina-15/fisiologia , Masculino , Força Muscular/genética , Músculo Esquelético/anatomia & histologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos , População Branca/genética
9.
Mol Genet Genomic Med ; 5(5): 524-530, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28944236

RESUMO

BACKGROUND: The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism (rs4340) (ACE DIP) accounts for half of the variability in plasma ACE concentrations. ACE has been widely studied for its influence on sports performance; however, research on its influence in physical activity is limited and inconsistent. We examined the influence of the ACE DIP on physical activity among 461 European Americans. METHODS: Subjects completed the Paffenbarger Physical Activity Questionnaire for weekly walking distance. Multivariate analysis of covariance (MANCOVA) tested log-transformed differences in weekly walking distance among ACE DIP genotypes (II, ID, DD) with gender as a fixed factor, and age and body mass index (BMI) as covariates. Because we found a significant ACE DIPxBMI interaction (P = 0.03), we categorized the sample by normal weight (NW: BMI<25.0 kg/m2) and overweight (OW: BMI ≥25.0 kg/m2) and repeated the MANCOVA with multiple comparison adjustments. RESULTS: NW adults with ACE II walked 15.8 ± 11.1 km/week, ID 13.2 ± 10.6 km/week, and DD 17.9 ± 13.0 km/week, with ID walking less than II (P = 0.03) and DD (P = 0.01). OW adults with ACE II walked 16.7 ± 12.6 km/week, ID 13.8 ± 11.6 km/week, and DD 9.7 ± 9.0 km/week, with DD walking less than II (P = 0.02). Weekly walking distance was 8.2 ± 2.4 km/week less among OW adults with ACE DD than NW (P = 0.02). CONCLUSION: BMI interacted with ACE DD such that OW walked ~8.2 km/week less than NW, potentially equating to a body weight differential of ~3.5 kg annually.

10.
Appl Physiol Nutr Metab ; 42(3): 278-284, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28177749

RESUMO

Studies of physical activity behaviours have increasingly shown the importance of heritable factors such as genetic variation. Nonsynonymous polymorphisms of alpha-actinin 3 (ACTN3) and the ß-adrenergic receptors 1 and 3 (ADRB1 and ADRB3) have been previously associated with exercise capacity and cardiometabolic health. We thus hypothesized that these polymorphisms are also related to physical activity behaviours in young adults. To test this hypothesis we examined relationships between ACTN3 (R577X), ARDB1 (Arg389Gly), ADRB3 (Trp64Arg), and physical activity behaviours in university students. We stratified for student enrollment in kinesiology degree programs compared with nonmajors as we previously found this to be a predictor of physical activity. We did not identify novel associations between physical activity and ACTN3. However, the minor alleles of ADRB1 and ADRB3 were significantly underrepresented in kinesiology students compared with nonmajors. Furthermore, carriers of the ADRB1 minor allele reported reduced participation in moderate physical activity and increased afternoon fatigue compared with ancestral allele homozygotes. Together, these findings suggest that the heritability of physical activity behaviours in young adults may be linked to nonsynonymous polymorphisms within ß-adrenergic receptors.


Assuntos
Actinina/genética , Exercício Físico , Comportamentos Relacionados com a Saúde , Cinesiologia Aplicada/educação , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 3/genética , Adolescente , Adulto , Alelos , Glicemia/metabolismo , Colesterol/sangue , Estudos de Coortes , Dieta , Feminino , Loci Gênicos , Marcadores Genéticos , Técnicas de Genotipagem , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Estudantes , Inquéritos e Questionários , Triglicerídeos/sangue , Adulto Jovem
11.
Am J Med Genet A ; 173(2): 501-509, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27797444

RESUMO

We describe a patient with failure to thrive, hepatomegaly, liver dysfunction, and elevation of multiple plasma lysosomal enzyme activities mimicking mucolipidosis II or III, in whom a diagnosis of hereditary fructose intolerance (HFI) was ultimately obtained. She presented before introduction of solid foods, given her consumption of a fructose-containing infant formula. We present the most extensive panel of lysosomal enzyme activities reported to date in a patient with HFI, and propose that multiple enzyme elevations in plasma, especially when in conjunction with a normal plasma α-mannosidase activity, should elicit a differential diagnosis of HFI. We also performed a review of the literature on the different etiologies of elevated lysosomal enzyme activities in serum or plasma. © 2016 Wiley Periodicals, Inc.


Assuntos
Intolerância à Frutose/diagnóstico , Mucolipidoses/diagnóstico , Biomarcadores/sangue , Diagnóstico Diferencial , Ativação Enzimática , Feminino , Intolerância à Frutose/sangue , Intolerância à Frutose/genética , Humanos , Lactente , Leucócitos/enzimologia , Lisossomos/enzimologia , Mucolipidoses/sangue , Mucolipidoses/genética , Fenótipo
12.
Ann Neurol ; 79(6): 1031-1037, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27159321

RESUMO

Here we report whole exome sequencing (WES) on a cohort of 71 patients with persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. WES analyses were performed on trio, or greater, family groups. Diagnostic pathogenic variants were identified in 35% (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7% (5 of 71) of cases, giving a total yield of clinical diagnoses in 42% of individuals. These findings provide evidence that WES can substantially decrease the number of unresolved white matter cases. Ann Neurol 2016;79:1031-1037.


Assuntos
Análise Mutacional de DNA , Exoma/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Substância Branca/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Leucoencefalopatias/patologia , Masculino , Mutação , Adulto Jovem
13.
PLoS One ; 11(1): e0148112, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26821164

RESUMO

Glucocorticoid receptor (NR3C1) polymorphisms associate with obesity, muscle strength, and cortisol sensitivity. We examined associations among four NR3C1 polymorphisms and the muscle response to resistance training (RT). European-American adults (n = 602, 23.8±0.4yr) completed a 12 week unilateral arm RT program. Maximum voluntary contraction (MVC) assessed isometric strength (kg) and MRI assessed biceps size (cm2) pre- and post-resistance training. Subjects were genotyped for NR3C1 -2722G>A, -1887G>A, -1017T>C, and +363A>G. Men carrying the -2722G allele gained less relative MVC (17.3±1.2vs33.5±6.1%) (p = 0.010) than AA homozygotes; men with -1887GG gained greater relative MVC than A allele carriers (19.6±1.4vs13.2±2.3%) (p = 0.016). Women carrying the -1017T allele gained greater relative size (18.7±0.5vs16.1±0.9%) (p = 0.016) than CC homozygotes. We found sex-specific NR3C1 associations with the muscle strength and size response to RT. Future studies should investigate whether these associations are partially explained by cortisol's actions in muscle tissue as they interact with sex differences in cortisol production.


Assuntos
Força Muscular , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/fisiologia , Receptores de Glucocorticoides/genética , Treinamento Resistido , Adulto , Feminino , Humanos , Masculino , Contração Muscular , Polimorfismo de Nucleotídeo Único , Adulto Jovem
14.
Sci Rep ; 5: 18369, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26670709

RESUMO

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency. The purpose of this study is to determine if functional single nucleotide polymorphisms (SNPs) in immune-modulating genes pre-dispose infants to NEC. After Institutional Review Board approval and parental consent, buccal swabs were collected for DNA extraction. TaqMan allelic discrimination assays and BglII endonuclease digestion were used to genotype specific inflammatory cytokines and TRIM21. Statistical analysis was completed using logistic regression. 184 neonates were analyzed in the study. Caucasian neonates with IL-6 (rs1800795) were over 6 times more likely to have NEC (p = 0.013; OR = 6.61, 95% CI 1.48-29.39), and over 7 times more likely to have Stage III disease (p = 0.011; OR = 7.13, (95% CI 1.56-32.52). Neonates with TGFß-1 (rs2241712) had a decreased incidence of NEC-related perforation (p = 0.044; OR = 0.28, 95% CI: 0.08-0.97) and an increased incidence of mortality (p = 0.049; OR = 2.99, 95% CI: 1.01 - 8.86). TRIM21 (rs660) was associated with NEC-related intestinal perforation (p = 0.038; OR = 4.65, 95% CI 1.09-19.78). In premature Caucasian neonates, the functional SNP IL-6 (rs1800795) is associated with both the development and increased severity of NEC. TRIM21 (rs660) and TGFß-1 (rs2241712) were associated with NEC- related perforation in all neonates in the cohort. These findings suggest a possible genetic role in the development of NEC.


Assuntos
Enterocolite Necrosante , Interleucina-6 , Polimorfismo de Nucleotídeo Único/imunologia , Ribonucleoproteínas , Fator de Crescimento Transformador beta1 , Enterocolite Necrosante/genética , Enterocolite Necrosante/imunologia , Feminino , Humanos , Recém-Nascido , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Ribonucleoproteínas/genética , Ribonucleoproteínas/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia
15.
Sports Med Open ; 1(1): 34, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26495240

RESUMO

BACKGROUND: Meta-analysis of genome-wide association studies identified obesity-related genetic variants. Due to the pleiotropic effects of related phenotypes, we tested six of these obesity-related genetic variants for their association with physical activity: fat mass and obesity-associated (FTO)(rs9939609)T>A, potassium channel tetramerization domain containing (KCTD15) (rs11084753)G>A, melanocortin receptor4 (MC4R)(rs17782313)T>C, neuronal growth regulator 1 (NEGR1)(rs2815752)A>G, SH2B adapter protein 1 (SH2B1)(rs7498665)A>G, and transmembrane protein18 (TMEM18)(rs6548238)C>T. METHOD: European-American women (n = 263) and men (n = 229) (23.5 ± 0.3 years, 24.6 ± 0.2 kg/m2) were genotyped and completed the Paffenbarger physical activity Questionnaire. Physical activity volume in metabolic energy equivalents [MET]-hour/week was derived from the summed time spent (hour/week) times the given MET value for vigorous, moderate, and light intensity physical activity, and sitting and sleeping, respectively. Multivariable adjusted [(age, sex, and body mass index (BMI)] linear regression tested associations among genotype (dominant/recessive model) and the log of physical activity volume. RESULT: MC4R (rs17782313)T>C explained 1.1 % (p = 0.02), TMEM18(rs6548238)C>T 1.2 % (p = 0.01), and SH2B1 (rs7498665)A>G 0.6 % (p = 0.08) of the variability in physical activity volume. Subjects with the MC4R C allele spent 3.5 % less MET-hour/week than those with the TT genotype (p = 0.02). Subjects with the TMEM18 T allele spent 4.1 % less MET-hour/week than those with the CC genotype (p = 0.01). Finally, subjects with the SH2B1 GG genotype spent 3.6 % less MET-hour/week than A allele carriers (p = 0.08). CONCLUSION: Our findings suggest a shared genetic influence among some obesity-related gene loci and physical activity phenotypes that should be explored further. Physical activity volume differences by genotype have public health importance equating to 11-13 lb weight difference annually.

16.
Mil Med ; 180(9): 1001-5, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26327553

RESUMO

OBJECTIVE: Muscle-specific creatine kinase is thought to play an integral role in maintaining energy homeostasis by providing a supply of creatine phosphate. The genetic variant, rs8111989, contributes to individual differences in physical performance, and thus the purpose of this study was to determine if rs8111989 variant is predictive of Physical Fitness Test (PFT) scores in male, military infantry recruits. METHODS: DNA was extracted from whole blood, and genotyping was performed in 176 Marines. Relationships between PFT measures (run, sit-ups, and pull-ups) and genotype were determined. RESULTS: Participants with 2 copies of the T allele for rs8111989 variant had higher PFT scores for run time, pull-ups, and total PFT score. Specifically, participants with 2 copies of the TT allele (variant) (n = 97) demonstrated an overall higher total PFT score as compared with those with one copy of the C allele (n = 79) (TT: 250 ± 31 vs. CC/CT: 238 ± 31; p = 0.02), run score (TT: 82 ± 10 vs. CC/CT: 78 ± 11; p = 0.04) and pull-up score (TT: 78 ± 11 vs. CC/CT: 65 ± 21; p = 0.04) or those with the CC/CT genotype. CONCLUSION: These results demonstrate an association between physical performance measures and genetic variation in the muscle-specific creatine kinase gene (rs8111989).


Assuntos
Creatina Quinase Forma MM/genética , Militares , Aptidão Física , Adolescente , Teste de Esforço , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estados Unidos , Adulto Jovem
17.
Acta Neuropathol ; 130(4): 575-85, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26264609

RESUMO

Among brain tumors, the BRAF (V600E) mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5 % of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF (V600) mutation rate is 36 %. V600-mutant tumors demonstrate a predilection for infants and young children (

Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Diencéfalo/patologia , Glioma/genética , Glioma/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Fatores Etários , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Estudos de Coortes , Inibidor p16 de Quinase Dependente de Ciclina/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Glioma/epidemiologia , Glioma/terapia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Mutação , Gradação de Tumores , Resultado do Tratamento
18.
PLoS One ; 10(6): e0130644, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26107372

RESUMO

Homozygosity for a premature stop codon (X) in the ACTN3 "sprinter" gene is common in humans despite the fact that it reduces muscle size, strength and power. Because of the close relationship between skeletal muscle function and cardiometabolic health we examined the influence of ACTN3 R577X polymorphism over cardiovascular and metabolic characteristics of young adults (n = 98 males, n = 102 females; 23 ± 4.2 years) from our Assessing Inherent Markers for Metabolic syndrome in the Young (AIMMY) study. Both males and females with the RR vs XX genotype achieved higher mean VO2 peak scores (47.8 ± 1.5 vs 43.2 ±1.8 ml/O2/min, p = 0.002) and exhibited higher resting systolic (115 ± 2 vs 105 ± mmHg, p = 0.027) and diastolic (69 ± 3 vs 59 ± 3 mmHg, p = 0.005) blood pressure suggesting a role for ACTN3 in the maintenance of vascular tone. We subsequently identified the expression of alpha-actinin 3 protein in pulmonary artery smooth muscle, which may explain the genotype-specific differences in cardiovascular adaptation to acute exercise. In addition, we utilized targeted serum metabolomics to distinguish between RR and XX genotypes, suggesting an additional role for the ACTN3 R577X polymorphism in human metabolism. Taken together, these results identify significant cardiometabolic effects associated with possessing one or more functional copies of the ACTN3 gene.


Assuntos
Actinina/genética , Desempenho Atlético/fisiologia , Músculo Liso/fisiologia , Resistência Física/genética , Polimorfismo de Nucleotídeo Único , Actinina/metabolismo , Adulto , Pressão Sanguínea/fisiologia , Exercício Físico/fisiologia , Feminino , Expressão Gênica , Genótipo , Humanos , Masculino , Contração Muscular/fisiologia , Músculo Esquelético/fisiologia , Artéria Pulmonar/fisiologia , Testes de Função Respiratória
19.
Eur J Clin Invest ; 45(4): 394-404, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25682967

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are noncoding RNA molecules that play important roles in the pathogenesis of various kidney diseases. We investigated whether patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) have distinct circulating and urinary miRNA expression profiles that could lead to potential development of noninvasive biomarkers of the disease. MATERIALS AND METHODS: Exosome miRNAs were extracted from plasma and urine samples of patients with primary FSGS (n = 16) or MCD (n = 5) and healthy controls (n = 5). Differences in miRNA abundance were examined using Affymetrix GeneChip miRNA 3.0 arrays. QRT-PCR was used to validate the findings from the array. RESULTS: Comparison analysis of FSGS versus MCD revealed 126 and 155 differentially expressed miRNAs in plasma and in urine, respectively. Only 38 of these miRNAs were previously cited, whereas the remaining miRNAs have not been described. Comparison analysis showed that a significant number of miRNAs were downregulated in both plasma and urine samples of patients with FSGS compared to those with MCD. Plasma levels of miR-30b, miR-30c, miR-34b, miR-34c and miR-342 and urine levels of mir-1225-5p were upregulated in patients with MCD compared to patients with FSGS and controls (P < 0.001). Urinary levels of mir-1915 and miR-663 were downregulated in patients with FSGS compared to MCD and controls (P < 0.001), whereas the urinary levels of miR-155 were upregulated in patients with FSGS when compared to patients with MCD and controls (P < 0.005). CONCLUSIONS: Patients with FSGS and MCD have a unique circulating and urinary miRNA profile. The diagnostic and prognostic potential of miRNAs in FSGS and MCD warrants further studies.


Assuntos
Glomerulosclerose Segmentar e Focal/genética , MicroRNAs/genética , Nefrose Lipoide/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Glomerulosclerose Segmentar e Focal/sangue , Glomerulosclerose Segmentar e Focal/urina , Humanos , Lactente , Masculino , MicroRNAs/sangue , MicroRNAs/urina , Pessoa de Meia-Idade , Nefrose Lipoide/sangue , Nefrose Lipoide/urina , Análise de Sequência com Séries de Oligonucleotídeos , Projetos Piloto , Adulto Jovem
20.
Cereb Cortex ; 25(2): 336-45, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23968837

RESUMO

Individual differences in striatal dopamine (DA) signaling have been associated both with individual differences in executive function in healthy individuals and with risk for psychiatric disorders defined by executive dysfunction. We used resting-state functional connectivity in 50 healthy adults to examine whether a polymorphism of the dopamine transporter gene (DAT1), which regulates striatal DA function, affects striatal functional connectivity in healthy adults, and whether that connectivity predicts executive function. We found that 9/10 heterozygotes, who are believed to have higher striatal DA signaling, demonstrated stronger connectivity between dorsal caudate (DC) and insular, dorsal anterior cingulate, and dorsolateral prefrontal regions, as well as between ventral striatum and ventrolateral prefrontal cortex, than 10/10 homozygotes. Across subjects, stronger DC-seeded connectivity predicted superior N-back working memory performance, while stronger ventral striatum-seeded connectivity predicted reduced impulsivity in everyday life. Further, mediation analysis suggested that connectivity strength mediated relationships between DAT1 genotype and behavior. These findings suggest that resting-state striato-frontal connectivity may be an endophenotype for executive function in healthy individuals.


Assuntos
Corpo Estriado/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Função Executiva , Lobo Frontal/fisiologia , Polimorfismo Genético , Mapeamento Encefálico , Feminino , Técnicas de Genotipagem , Heterozigoto , Humanos , Comportamento Impulsivo , Imageamento por Ressonância Magnética , Masculino , Memória de Curto Prazo , Vias Neurais/fisiologia , Testes Psicológicos , Descanso , Adulto Jovem
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