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1.
Blood ; 128(8): 1121-8, 2016 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-27365426

RESUMO

We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio [OR] = 2.4, P = 6.6 × 10(-89)), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 × 10(-32)), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 × 10(-14)), and upstream of TET2 (rs1548483: OR = 2.0, P = 2.0 × 10(-9)). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.


Assuntos
Predisposição Genética para Doença , Células Germinativas/metabolismo , Hematopoese/genética , Janus Quinase 2/genética , Mutação/genética , Transtornos Mieloproliferativos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Demografia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Adulto Jovem
3.
PLoS Genet ; 9(2): e1003299, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23468642

RESUMO

Myopia, or nearsightedness, is the most common eye disorder, resulting primarily from excess elongation of the eye. The etiology of myopia, although known to be complex, is poorly understood. Here we report the largest ever genome-wide association study (45,771 participants) on myopia in Europeans. We performed a survival analysis on age of myopia onset and identified 22 significant associations ([Formula: see text]), two of which are replications of earlier associations with refractive error. Ten of the 20 novel associations identified replicate in a separate cohort of 8,323 participants who reported if they had developed myopia before age 10. These 22 associations in total explain 2.9% of the variance in myopia age of onset and point toward a number of different mechanisms behind the development of myopia. One association is in the gene PRSS56, which has previously been linked to abnormally small eyes; one is in a gene that forms part of the extracellular matrix (LAMA2); two are in or near genes involved in the regeneration of 11-cis-retinal (RGR and RDH5); two are near genes known to be involved in the growth and guidance of retinal ganglion cells (ZIC2, SFRP1); and five are in or near genes involved in neuronal signaling or development. These novel findings point toward multiple genetic factors involved in the development of myopia and suggest that complex interactions between extracellular matrix remodeling, neuronal development, and visual signals from the retina may underlie the development of myopia in humans.


Assuntos
Matriz Extracelular , Olho , Estudo de Associação Genômica Ampla , Miopia , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Olho/metabolismo , Olho/fisiopatologia , Predisposição Genética para Doença , Humanos , Miopia/genética , Miopia/patologia , Neurônios/metabolismo , Neurônios/patologia , Erros de Refração/genética , Erros de Refração/metabolismo , Erros de Refração/patologia , Retina/metabolismo , Retina/patologia , Células Ganglionares da Retina/metabolismo , Serina Proteases/genética
5.
PLoS Genet ; 8(10): e1002973, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23071447

RESUMO

The clinical utility of family history and genetic tests is generally well understood for simple Mendelian disorders and rare subforms of complex diseases that are directly attributable to highly penetrant genetic variants. However, little is presently known regarding the performance of these methods in situations where disease susceptibility depends on the cumulative contribution of multiple genetic factors of moderate or low penetrance. Using quantitative genetic theory, we develop a model for studying the predictive ability of family history and single nucleotide polymorphism (SNP)-based methods for assessing risk of polygenic disorders. We show that family history is most useful for highly common, heritable conditions (e.g., coronary artery disease), where it explains roughly 20%-30% of disease heritability, on par with the most successful SNP models based on associations discovered to date. In contrast, we find that for diseases of moderate or low frequency (e.g., Crohn disease) family history accounts for less than 4% of disease heritability, substantially lagging behind SNPs in almost all cases. These results indicate that, for a broad range of diseases, already identified SNP associations may be better predictors of risk than their family history-based counterparts, despite the large fraction of missing heritability that remains to be explained. Our model illustrates the difficulty of using either family history or SNPs for standalone disease prediction. On the other hand, we show that, unlike family history, SNP-based tests can reveal extreme likelihood ratios for a relatively large percentage of individuals, thus providing potentially valuable adjunctive evidence in a differential diagnosis.


Assuntos
Predisposição Genética para Doença , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Família , Humanos , Funções Verossimilhança , Modelos Genéticos , Linhagem , Curva ROC , Risco
6.
Proc Natl Acad Sci U S A ; 109(1): 215-20, 2012 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-22178754

RESUMO

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the gene coding for FIBRILLIN-1 (FBN1), an extracellular matrix protein. MFS is inherited as an autosomal dominant trait and displays major manifestations in the ocular, skeletal, and cardiovascular systems. Here we report molecular and phenotypic profiles of skeletogenesis in tissues differentiated from human embryonic stem cells and induced pluripotent stem cells that carry a heritable mutation in FBN1. We demonstrate that, as a biological consequence of the activation of TGF-ß signaling, osteogenic differentiation of embryonic stem cells with a FBN1 mutation is inhibited; osteogenesis is rescued by inhibition of TGF-ß signaling. In contrast, chondrogenesis is not perturbated and occurs in a TGF-ß cell-autonomous fashion. Importantly, skeletal phenotypes observed in human embryonic stem cells carrying the monogenic FBN1 mutation (MFS cells) are faithfully phenocopied by cells differentiated from induced pluripotent-stem cells derived independently from MFS patient fibroblasts. Results indicate a unique phenotype uncovered by examination of mutant pluripotent stem cells and further demonstrate the faithful alignment of phenotypes in differentiated cells obtained from both human embryonic stem cells and induced pluripotent-stem cells, providing complementary and powerful tools to gain further insights into human molecular pathogenesis, especially of MFS.


Assuntos
Osso e Ossos/patologia , Células-Tronco Embrionárias/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Síndrome de Marfan/patologia , Sequência de Bases , Osso e Ossos/metabolismo , Diferenciação Celular , Condrogênese , Células-Tronco Embrionárias/metabolismo , Fibrilina-1 , Fibrilinas , Humanos , Síndrome de Marfan/metabolismo , Proteínas dos Microfilamentos/genética , Dados de Sequência Molecular , Osteogênese , Fenótipo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
7.
PLoS Genet ; 8(2): e1002458, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22319452

RESUMO

A hallmark feature of Williams-Beuren Syndrome (WBS) is a generalized arteriopathy due to elastin deficiency, presenting as stenoses of medium and large arteries and leading to hypertension and other cardiovascular complications. Deletion of a functional NCF1 gene copy has been shown to protect a proportion of WBS patients against hypertension, likely through reduced NADPH-oxidase (NOX)-mediated oxidative stress. DD mice, carrying a 0.67 Mb heterozygous deletion including the Eln gene, presented with a generalized arteriopathy, hypertension, and cardiac hypertrophy, associated with elevated angiotensin II (angII), oxidative stress parameters, and Ncf1 expression. Genetic (by crossing with Ncf1 mutant) and/or pharmacological (with ang II type 1 receptor blocker, losartan, or NOX inhibitor apocynin) reduction of NOX activity controlled hormonal and biochemical parameters in DD mice, resulting in normalized blood pressure and improved cardiovascular histology. We provide strong evidence for implication of the redox system in the pathophysiology of the cardiovascular disease in a mouse model of WBS. The phenotype of these mice can be ameliorated by either genetic or pharmacological intervention reducing NOX activity, likely through reduced angII-mediated oxidative stress. Therefore, anti-NOX therapy merits evaluation to prevent the potentially serious cardiovascular complications of WBS, as well as in other cardiovascular disorders mediated by similar pathogenic mechanism.


Assuntos
Angiotensina II/metabolismo , Elastina/genética , NADPH Oxidases/metabolismo , Estresse Oxidativo , Síndrome de Williams/genética , Acetofenonas/farmacologia , Angiotensina II/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Artérias/patologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Cardiomegalia/patologia , Constrição Patológica/patologia , Modelos Animais de Doenças , Elastina/deficiência , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Hipertensão/patologia , Losartan/farmacologia , Camundongos , NADPH Oxidases/genética , Deleção de Sequência , Síndrome de Williams/metabolismo , Síndrome de Williams/patologia , Síndrome de Williams/fisiopatologia
8.
PLoS Genet ; 7(6): e1002141, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21738487

RESUMO

Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.


Assuntos
Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Internet , Doença de Parkinson/genética , Bases de Dados Factuais , Predisposição Genética para Doença , Hereditariedade/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Medição de Risco
9.
BMC Med Genet ; 13: 53, 2012 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-22747683

RESUMO

BACKGROUND: While some factors of breast morphology, such as density, are directly implicated in breast cancer, the relationship between breast size and cancer is less clear. Breast size is moderately heritable, yet the genetic variants leading to differences in breast size have not been identified. METHODS: To investigate the genetic factors underlying breast size, we conducted a genome-wide association study (GWAS) of self-reported bra cup size, controlling for age, genetic ancestry, breast surgeries, pregnancy history and bra band size, in a cohort of 16,175 women of European ancestry. RESULTS: We identified seven single-nucleotide polymorphisms (SNPs) significantly associated with breast size (p<5.10(-8)): rs7816345 near ZNF703, rs4849887 and (independently) rs17625845 flanking INHBB, rs12173570 near ESR1, rs7089814 in ZNF365, rs12371778 near PTHLH, and rs62314947 near AREG. Two of these seven SNPs are in linkage disequilibrium (LD) with SNPs associated with breast cancer (those near ESR1 and PTHLH), and a third (ZNF365) is near, but not in LD with, a breast cancer SNP. The other three loci (ZNF703, INHBB, and AREG) have strong links to breast cancer, estrogen regulation, and breast development. CONCLUSIONS: These results provide insight into the genetic factors underlying normal breast development and show that some of these factors are shared with breast cancer. While these results do not directly support any possible epidemiological relationships between breast size and cancer, this study may contribute to a better understanding of the subtle interactions between breast morphology and breast cancer risk.


Assuntos
Neoplasias da Mama/genética , Mama/anatomia & histologia , Mama/metabolismo , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Mama/crescimento & desenvolvimento , Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Tamanho do Órgão/genética , Gravidez
10.
Nature ; 441(7093): 595-600, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16554754

RESUMO

Trisomy 21 results in Down's syndrome, but little is known about how a 1.5-fold increase in gene dosage produces the pleiotropic phenotypes of Down's syndrome. Here we report that two genes, DSCR1 and DYRK1A , lie within the critical region of human chromosome 21 and act synergistically to prevent nuclear occupancy of NFATc transcription factors, which are regulators of vertebrate development. We use mathematical modelling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. Our observations of calcineurin-and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down's syndrome and human trisomy 21 are consistent with these predictions. We suggest that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down's syndrome. More generally, these observations suggest that the destabilization of regulatory circuits can underlie human disease.


Assuntos
Cromossomos de Mamíferos/genética , Síndrome de Down/genética , Dosagem de Genes/genética , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Musculares/genética , Fatores de Transcrição NFATC/metabolismo , Proteínas Serina-Treonina Quinases/genética , Animais , Proteínas de Ligação ao Cálcio , Cromossomos Humanos Par 21/genética , Modelos Animais de Doenças , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Transgênicos , Modelos Genéticos , Proteínas Musculares/metabolismo , Mutação/genética , Fatores de Transcrição NFATC/deficiência , Fatores de Transcrição NFATC/genética , Fenótipo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases , Transgenes/genética , Quinases Dyrk
11.
Am J Hum Genet ; 92(3): 325-37, 2013 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-23472754
12.
J Vasc Res ; 48(2): 119-29, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-20926892

RESUMO

AIMS: The Williams-Beuren syndrome (WBS) is a genetic disorder caused by a heterozygous ~1.5-Mb deletion. The aim of this study was to determine how the genetic changes in a Wbs mouse model alter Eln expression, blood pressure, vessel structure, and abdominal aortic wall dynamics in vivo. METHODS: Elastin (ELN) transcript levels were quantified by qRT-PCR and blood pressure was measured with a tail cuff system. M-mode ultrasound was used to track pulsatile abdominal aortic wall motion. Aortas were sectioned and stained to determine medial lamellar structure. RESULTS: ELN transcript levels were reduced by 38-41% in Wbs mice lacking one copy of the ELN gene. These mice also had a 10-20% increase in mean blood pressure and significantly reduced circumferential cyclic strain (p < 0.001). Finally, histological sections showed disorganized and fragmented elastin sheets in Wbs mice, but not the characteristic increase in lamellar units seen in Eln(+/-) mice. CONCLUSIONS: The deletion of Eln in this Wbs mouse model results in lower gene expression, hypertension, reduced cyclic strain, and fragmented elastin sheets. The observation that the number of medial lamellar units is normal in Wbs deletion mice, which is in contrast to Eln(+/-) mice, suggests other genes may be involved in vascular development.


Assuntos
Pressão Sanguínea/genética , Deleção Cromossômica , Elastina/genética , Elastina/metabolismo , Síndrome de Williams/genética , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/ultraestrutura , Anormalidades Cardiovasculares/genética , Anormalidades Cardiovasculares/metabolismo , Modelos Animais de Doenças , Elasticidade , Feminino , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Ultrassonografia , Síndrome de Williams/metabolismo , Síndrome de Williams/fisiopatologia
13.
Pediatr Res ; 69(3): 265-70, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21135753

RESUMO

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder. Diagnostic criteria of neonatal MFS (nMFS), the most severe form, are still debated. The aim of our study was to search for clinical and molecular prognostic factors that could be associated with length of survival. Probands ascertained via the framework of the Universal Marfan database-FBN1, diagnosed before the age of 1 y and presenting with cardiovascular features (aortic root dilatation or valvular insufficiency) were included in this study. Clinical and molecular data were correlated to survival. Among the 60 individuals, 38 had died, 82% died before the age of 1 y, mostly because of congestive heart failure. Three probands reached adulthood. Valvular insufficiencies and diaphragmatic hernia were predictive of shorter life expectancy. Two FBN1 mutations were found outside of the exon 24-32 region (in exons 4 and 21). Mutations in exons 25-26 were overrepresented and were associated with shorter survival (p = 0.03). We report the largest genotyped series of probands with MFS diagnosed before 1 y of life. In this population, factors significantly associated with shorter survival are presence of valvular insufficiencies or diaphragmatic hernia in addition to a mutation in exons 25 or 26.


Assuntos
Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Mutação , Pré-Escolar , Bases de Dados Factuais , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Síndrome de Marfan/mortalidade , Prognóstico
14.
Eur Heart J ; 31(18): 2223-9, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20709720

RESUMO

AIMS: In patients with Marfan syndrome and other type-1 fibrillinopathies, genetic testing is becoming more easily available, leading to the identification of mutations early in the course of the disease. This study evaluates the cardiovascular (CV) risk associated with the discovery of a fibrillin-1 (FBN1) mutation. METHODS AND RESULTS: A total of 1,013 probands with pathogenic FBN1 mutations were included, among whom 965 patients [median age: 22 years (11-34), male gender 53%] had data suitable for analysis. The percentage of patients with an ascending aortic (AA) dilatation increased steadily with increasing age and reached 96% (95% CI: 94-97%) by 60 years. The presence of aortic events (dissection or prophylactic surgery) was rare before 20 years and then increased progressively, reaching 74% (95% CI: 67-81%) by 60 years. Compared with women, men were at higher risk for AA dilatation [≤ 30 years: 57% (95% CI: 52-63) vs. 50% (95% CI: 45-55), P = 0.0076] and aortic events [≤ 30 years: 21% (95% CI: 17-26) vs. 11% (95% CI: 8-16), P < 0.0001; adjusted HR: 1.4 (1.1-1.8), P = 0.005]. The prevalence of mitral valve (MV) prolapse [≤ 60 years: 77% (95% CI: 72-82)] and MV regurgitation [≤ 60 years: 61% (95% CI: 53-69)] also increased steadily with age, but surgery limited to the MV remained rare [≤ 60 years: 13% (95% CI: 8-21)]. No difference between genders was observed (for all P> 0.20). From 1985 to 2005 the prevalence of AA dilatation remained stable (P for trend = 0.88), whereas the percentage of patients with AA dissection significantly decreased (P for trend = 0.01). CONCLUSION: The CV risk remains important in patients with an FBN1 gene mutation and is present throughout life, justifying regular aortic monitoring. Aortic dilatation or dissection should always trigger suspicion of a genetic background leading to thorough examination for extra-aortic features and comprehensive pedigree investigation.


Assuntos
Aneurisma Aórtico/genética , Dissecção Aórtica/genética , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Prolapso da Valva Mitral/genética , Mutação/genética , Adolescente , Adulto , Criança , Feminino , Fibrilina-1 , Fibrilinas , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
15.
Mol Genet Genomic Med ; 8(11): e1468, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32940023

RESUMO

BACKGROUND: Clinical genetic testing for inherited predisposition to venous thromboembolism (VTE) is common among patients and their families. However, there is incomplete consensus about which individuals should receive testing, and the relative risks and benefits. METHODS: We assessed outcomes of receiving direct-to-consumer (DTC) results for the two most common genetic risk factors for VTE, factor V Leiden in the F5 gene (FVL) and prothrombin 20210G>A in the F2 gene (PT). Two thousand three hundred fifty-four customers (1244 variant-positive and 1110 variant-negative individuals) of the personal genetics company 23andMe, Inc., who had received results online for F5 and F2 variants, participated in an online survey-based study. Participants responded to questions about perception of VTE risk, discussion of results with healthcare providers (HCPs) and recommendations received, actions taken to control risk, emotional responses to receiving risk results, and perceived value of the information. RESULTS: Most participants (90% of variant-positive individuals, 99% of variant-negative individuals) had not previously been tested for F5 and/or F2 variants. The majority of variant-positive individuals correctly perceived that they were at higher than average risk for developing VTE. These individuals reported moderate rates of discussing results with HCPs (41%); receiving prevention advice from HCPs (31%), and making behavioral changes to control risk (e.g., exercising more, 30%). A minority (36%) of variant-positive individuals worried more after receiving VTE results. Nevertheless, most participants reported that knowing their risk had been an advantage (78% variant-positive and 58% variant-negative) and were satisfied knowing their genetic probability for VTE (81% variant-positive and 67% variant-negative). CONCLUSION: Consumers reported moderate rates of behavioral change and perceived personal benefit from receiving DTC genetic results for VTE risk.


Assuntos
Atitude , Triagem e Testes Direto ao Consumidor/psicologia , Fator V/genética , Testes Genéticos/estatística & dados numéricos , Protrombina/genética , Adulto , Triagem e Testes Direto ao Consumidor/estatística & dados numéricos , Feminino , Frequência do Gene , Comportamentos Relacionados com a Saúde , Heterozigoto , Humanos , Masculino , Pacientes/psicologia
16.
J Pediatr Genet ; 9(1): 58-62, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31976146

RESUMO

Roberts syndrome is a rare autosomal recessive genetic disease. In this report, we report a Brazilian patient with a rare ESCO2 variant. The patient manifested a broad range of clinical findings including the significant, bilateral shortening of the extremities. He deteriorated and passed away at 20 days of age. High-resolution GTG-banded karyotype showed lack of centromeric constriction in some chromosomes, premature centromere separation in others, and repulsion of the heterochromatin regions. Molecular analysis of the ESCO2 gene revealed a deletion of 4 bp involving exon 4 in homozygosity (NM_00107420.2:c.875_878delACAG), which causes loss of ESCO2 function. We describe the clinical presentation caused by a rare ESCO2 variant.

17.
J Med Genet ; 44(2): 136-43, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16971481

RESUMO

BACKGROUND: During a genetic study of autism, a female child who met diagnostic criteria for autism spectrum disorder, but also exhibited the cognitive-behavioural profile (CBP) associated with Williams-Beuren syndrome (WBS) was examined. The WBS CBP includes impaired visuospatial ability, an overly friendly personality, excessive non-social anxiety and language delay. METHODS: Using array-based comparative genomic hybridisation (aCGH), a deletion corresponding to BAC RP11-89A20 in the distal end of the WBS deletion interval was detected. Hemizygosity was confirmed using fluorescence in situ hybridisation and fine mapping was performed by measuring the copy number of genomic DNA using quantitative polymerase chain reaction. RESULTS: The proximal breakpoint was mapped to intron 1 of GTF2IRD1 and the distal breakpoint lies 2.4-3.1 Mb towards the telomere. The subject was completely hemizygous for GTF2I, commonly deleted in carriers of the classic approximately 1.5 Mb WBS deletion, and GTF2IRD2, deleted in carriers of the rare approximately 1.84 Mb WBS deletion. CONCLUSION: Hemizygosity of the GTF2 family of transcription factors is sufficient to produce many aspects of the WBS CBP, and particularly implicate the GTF2 transcription factors in the visuospatial construction deficit. Symptoms of autism in this case may be due to deletion of additional genes outside the typical WBS interval or remote effects on gene expression at other loci.


Assuntos
Agnosia/genética , Transtorno Autístico/genética , Cromossomos Humanos Par 7 , Deleção de Sequência , Síndrome de Williams/genética , Feminino , Humanos , Íntrons , Fatores de Transcrição TFII/genética
18.
BMC Genomics ; 8: 319, 2007 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-17850668

RESUMO

BACKGROUND: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. RESULTS: We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. CONCLUSION: Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 x 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater.


Assuntos
Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Síndrome de Marfan/genética , Análise de Sequência com Séries de Oligonucleotídeos , Pele/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Variação Genética , Humanos , Modelos Biológicos , Fenótipo
19.
BMC Med Genet ; 8: 36, 2007 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-17584923

RESUMO

BACKGROUND: MeCP2, methyl-CpG-binding protein 2, binds to methylated cytosines at CpG dinucleotides, as well as to unmethylated DNA, and affects chromatin condensation. MECP2 mutations in females lead to Rett syndrome, a neurological disorder characterized by developmental stagnation and regression, loss of purposeful hand movements and speech, stereotypic hand movements, deceleration of brain growth, autonomic dysfunction and seizures. Most mutations occur de novo during spermatogenesis. Located at Xq28, MECP2 is subject to X inactivation, and affected females are mosaic. Rare hemizygous males suffer from a severe congenital encephalopathy. METHODS: To identify the pathways mis-regulated by MeCP2 deficiency, microarray-based global gene expression studies were carried out in cerebellum of Mecp2 mutant mice. We compared transcript levels in mutant/wildtype male sibs of two different MeCP2-deficient mouse models at 2, 4 and 8 weeks of age. Increased transcript levels were evaluated by real-time quantitative RT-PCR. Chromatin immunoprecipitation assays were used to document in vivo MeCP2 binding to promoter regions of candidate target genes. RESULTS: Of several hundred genes with altered expression levels in the mutants, twice as many were increased than decreased, and only 27 were differentially expressed at more than one time point. The number of misregulated genes was 30% lower in mice with the exon 3 deletion (Mecp2tm1.1Jae) than in mice with the larger deletion (Mecp2tm1.1Bird). Between the mutants, few genes overlapped at each time point. Real-time quantitative RT-PCR assays validated increased transcript levels for four genes: Irak1, interleukin-1 receptor-associated kinase 1; Fxyd1, phospholemman, associated with Na, K-ATPase;Reln, encoding an extracellular signaling molecule essential for neuronal lamination and synaptic plasticity; and Gtl2/Meg3, an imprinted maternally expressed non-translated RNA that serves as a host gene for C/D box snoRNAs and microRNAs. Chromatin immunoprecipitation assays documented in vivo MeCP2 binding to promoter regions of Fxyd1, Reln, and Gtl2. CONCLUSION: Transcriptional profiling of cerebellum failed to detect significant global changes in Mecp2-mutant mice. Increased transcript levels of Irak1, Fxyd1, Reln, and Gtl2 may contribute to the neuronal dysfunction in MeCP2-deficient mice and individuals with Rett syndrome. Our data provide testable hypotheses for future studies of the regulatory or signaling pathways that these genes act on.


Assuntos
Cerebelo/metabolismo , Expressão Gênica , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Animais , Moléculas de Adesão Celular Neuronais/genética , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Quinases Associadas a Receptores de Interleucina-1/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Proteínas do Tecido Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Fosfoproteínas/genética , Proteínas/genética , RNA Longo não Codificante , Proteína Reelina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina Endopeptidases/genética
20.
Nat Clin Pract Neurol ; 2(4): 212-21, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16932552

RESUMO

Rett syndrome (RTT) is unique among genetic, chromosomal and other developmental disorders because of its extreme female gender bias, early normal development, and subsequent developmental regression with loss of motor and language skills. RTT is caused by heterozygosity for mutations in the X-linked gene MECP2, which encodes methyl-CpG binding protein 2. MeCP2 is a multifunctional protein that can act as an architectural chromatin-binding protein, a function that is unrelated to its ability to bind methyl-CpG and to attract chromatin modification complexes. Inactivating mutations that cause RTT in females are not prenatally lethal in males, but lead to profound congenital encephalopathy. Molecular diagnoses of RTT, through demonstration of a MECP2 mutation, made at an early stage of the disorder, usually confirm the sporadic nature and very low recurrence risk of the condition. A positive DNA test result, however, also predicts the inevitable clinical course, given the lack of effective intervention. Initial hypotheses indicating that the MeCP2 protein acts as a genome-wide transcriptional repressor were not confirmed by global gene expression studies in various tissues of individuals with RTT and mouse models of MeCP2 deficiency. Rather, recent evidence points to low-magnitude effects of a small number of genes--including the brain--derived neurotrophic factor pathway and glucocorticoid response genes-that might affect formation and maturation of synapses or synaptic function in postmitotic neurons.


Assuntos
Proteína 2 de Ligação a Metil-CpG/deficiência , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/etiologia , Síndrome de Rett/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/uso terapêutico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Modelos Biológicos , Síndrome de Rett/tratamento farmacológico , Síndrome de Rett/patologia , Fatores Sexuais
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