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1.
BMC Med Genet ; 20(1): 71, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053111

RESUMO

BACKGROUND: Nail-patella syndrome (NPS) is an autosomal dominant developmental disorder most commonly characterized by dyplasia of nail or patella, the radial head or the humeral head hypoplasia, and, frequently ocular abnormalities and renal disease. It is caused by heterozygous loss-of-function mutations in the LMX1B gene, which encodes LIM homeodomain transcription factor and is essential for regulating the dorsal limb fate. METHODS: A five generation pedigree was recruited. Genomic DNA was extracted from the peripheral blood samples. Mutation detection was performed by Sanger sequencing the LMX1B gene. In silico functional annotation of the variant was performed using the in silico predictors SIFT, PolyPhen-2 and Mutation Taster. RESULTS: A novel heterozygous small deletion within exon 4 of LMX1B, c.712_714delTTC, was identified in a rare five-generation NPS pedigree. The mutation resulted in a deletion of the conserved amino acid phenylalanine at codon 238 (p.Phe238del), which located in the homeodomain of LMX1B may abolish DNA binding with the molecule. Conformational prediction showed that the variation could transform the helical structure comprising p.Phe234, p.Lys235, p.Ala236, and p.Ser237. CONCLUSION: We identified a novel NPS-causing LMX1B mutation and expanded the spectrum of mutations in the LMX1B gene. The c.712_714delTTC mutation may affect the quaternary structure of LMX1B, which is essential for the specification of dorsal limb fate at both zeugopodal and autopodal levels, leading to typical NPS.


Assuntos
Deleção de Genes , Proteínas com Homeodomínio LIM/genética , Síndrome da Unha-Patela/genética , Fatores de Transcrição/genética , China , Códon , Éxons , Feminino , Heterozigoto , Humanos , Mutação com Perda de Função , Masculino , Linhagem
2.
Am J Med Genet A ; 176(10): 2172-2181, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30289625

RESUMO

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

3.
Diabetes ; 67(5): 861-871, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29483183

RESUMO

Strong associations between HLA alleles and infectious and autoimmune diseases are well established. Although obesity is also associated with these diseases, the relationship between HLA and obesity has not been systematically investigated in a large cohort. In the current study, we analyzed the association of HLA alleles with BMI using data from 1.3 million healthy adult donors from the Chinese Marrow Donor Program (CMDP). We found 23 HLA alleles, including 12 low-resolution and 11 high-resolution alleles, were significantly associated with BMI after correction for multiple testing. Alleles associated with high BMI were enriched in haplotypes that were common in both Chinese and European populations, whereas the alleles associated with low BMI were enriched in haplotypes common only in Asians. Alleles B*07, DRB1*07, DRB1*12, and C*03:02 provided the strongest associations with BMI (P = 6.89 × 10-10, 1.32 × 10-9, 1.52 × 10-9, and 4.45 × 10-8, respectively), where B*07 and DRB1*07 also had evidence for sex-specific effects (Pheterogeneity = 0.0067 and 0.00058, respectively). These results, which identify associations between alleles of HLA-B, DRB1, and C with BMI in Chinese young adults, implicate a novel biological connection between HLA alleles and obesity.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Antígeno HLA-B7/genética , Antígenos HLA-C/genética , Cadeias HLA-DRB1/genética , Obesidade/genética , Adolescente , Adulto , Índice de Massa Corporal , China , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Sobrepeso/genética , Fenótipo , Fatores Sexuais , Adulto Jovem
4.
Hum Mol Genet ; 27(7): 1150-1163, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29361080

RESUMO

Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22A+, resulting in LCR22A+-B or LCR22A+-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22A+ region with a breakpoint in LCR22A+. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-A+ duplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22A+ maps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.

5.
PLoS One ; 12(11): e0188458, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29161311

RESUMO

Plants are continually exposed to a variety of pathogenic organisms, including bacteria, fungi and viruses. In response to these assaults, plants have developed various defense pathways to protect themselves from pathogen invasion. An understanding of the expression and regulation of genes involved in defense signaling is essential to controlling plant disease. ATL9, an Arabidopsis RING zinc finger protein, is an E3 ubiquitin ligase that is induced by chitin and involved in basal resistance to the biotrophic fungal pathogen, Golovinomyces cichoracearum (G. cichoracearum). To better understand the expression and regulation of ATL9, we studied its expression pattern and the functions of its different protein domains. Using pATL9:GUS transgenic Arabidopsis lines we found that ATL9 is expressed in numerous tissues at various developmental stages and that GUS activity was induced rapidly upon wounding. Using a GFP control protein, we showed that ATL9 is a short-lived protein within plant cells and it is degraded via the ubiquitin-proteasome pathway. ATL9 contains two transmembrane domains (TM), a RING zinc-finger domain, and a PEST domain. Using a series of deletion mutants, we found that the PEST domain and the RING domain have effects on ATL9 degradation. Further infection assays with G. cichoracearum showed that both the RING domain and the TM domains are important for ATL9's resistance phenotype. Interestingly, the PEST domain was also shown to be significant for resistance to fungal pathogens. This study demonstrates that the PEST domain is directly coupled to plant defense regulation and the importance of protein degradation in plant immunity.


Assuntos
Resistência à Doença/genética , Doenças das Plantas/genética , Plantas Geneticamente Modificadas/genética , Ubiquitina-Proteína Ligases/genética , Arabidopsis/genética , Arabidopsis/microbiologia , Quitina/química , Fungos/patogenicidade , Regulação da Expressão Gênica de Plantas , Doenças das Plantas/microbiologia , Plantas Geneticamente Modificadas/microbiologia , Domínios Proteicos/genética , Proteólise , Deleção de Sequência , Ubiquitina-Proteína Ligases/biossíntese
6.
Circ Cardiovasc Genet ; 10(5)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29025761

RESUMO

BACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort. METHODS AND RESULTS: To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, P=2.98×10-8) in an intron of the adhesion GPR98 (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with GPR98, including MEF2C (Myocyte-specific enhancer factor 2C). MEF2C is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS. CONCLUSIONS: In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.


Assuntos
Síndrome de DiGeorge/genética , Estudo de Associação Genômica Ampla , Receptores Acoplados a Proteínas-G/genética , Tetralogia de Fallot/genética , Cromatina/metabolismo , Cromossomos Humanos Par 5 , Síndrome de DiGeorge/complicações , Loci Gênicos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Desequilíbrio de Ligação , Fatores de Transcrição MEF2/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/metabolismo , Análise de Sequência de DNA , Tetralogia de Fallot/complicações
7.
Am J Psychiatry ; 174(11): 1054-1063, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28750581

RESUMO

OBJECTIVE: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. METHOD: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. RESULTS: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. CONCLUSIONS: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Transtornos Cromossômicos/genética , Síndrome de DiGeorge/genética , Deficiência Intelectual/genética , Esquizofrenia/genética , Adulto , Transtorno do Espectro Autista/psicologia , Transtorno Autístico/psicologia , Deleção Cromossômica , Transtornos Cromossômicos/psicologia , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/psicologia , Feminino , Humanos , Deficiência Intelectual/psicologia , Masculino , Pessoa de Meia-Idade
8.
PLoS Genet ; 13(3): e1006687, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28346476

RESUMO

The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of TBX1, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations. Inactivation of Tbx1 in the anterior heart field (AHF) mesoderm in the mouse results in premature expression of pro-differentiation genes and a persistent truncus arteriosus (PTA) in which septation does not form between the aorta and pulmonary trunk. Canonical Wnt/ß-catenin has major roles in cardiac OFT development that may act upstream of Tbx1. Consistent with an antagonistic relationship, we found the opposite gene expression changes occurred in the AHF in ß-catenin loss of function embryos compared to Tbx1 loss of function embryos, providing an opportunity to test for genetic rescue. When both alleles of Tbx1 and one allele of ß-catenin were inactivated in the Mef2c-AHF-Cre domain, 61% of them (n = 34) showed partial or complete rescue of the PTA defect. Upregulated genes that were oppositely changed in expression in individual mutant embryos were normalized in significantly rescued embryos. Further, ß-catenin was increased in expression when Tbx1 was inactivated, suggesting that there may be a negative feedback loop between canonical Wnt and Tbx1 in the AHF to allow the formation of the OFT. We suggest that alteration of this balance may contribute to variable expressivity in 22q11.2DS.


Assuntos
Anormalidades Cardiovasculares/genética , Síndrome de DiGeorge/genética , Modelos Animais de Doenças , Proteínas com Domínio T/genética , beta Catenina/genética , Animais , Apoptose/genética , Anormalidades Cardiovasculares/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/genética , Síndrome de DiGeorge/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Hibridização In Situ , Mesoderma/citologia , Mesoderma/embriologia , Mesoderma/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Microscopia de Fluorescência , Miócitos Cardíacos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas com Domínio T/metabolismo , Tronco Arterial/citologia , Tronco Arterial/embriologia , Tronco Arterial/metabolismo , beta Catenina/metabolismo
9.
Chem Biol Drug Des ; 89(1): 61-66, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27647631

RESUMO

Enzymatic glycosylation of sterols/steroids with glycosyltransferase HP0421 shows protein plasticity on generation of configurationally rare steryl-α-glucosides. Investigation of trans-androsteronyl-α-glucoside on tamoxifen-treated MCF-7 breast cancer cells shows dose-dependent depression of cell viability and enhanced drug effectiveness, illustrating a new avenue for the production of novel steryl-α-glucosides with useful biological activities.


Assuntos
Androsterona/química , Antineoplásicos/química , Glucosídeos/química , Antineoplásicos/farmacologia , Glucosídeos/farmacologia , Conformação Proteica
10.
Aging Cell ; 15(5): 811-24, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27329260

RESUMO

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.


Assuntos
Envelhecimento/genética , Estudo de Associação Genômica Ampla , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Característica Quantitativa Herdável , Adulto , Envelhecimento/sangue , Feminino , Regulação da Expressão Gênica , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Masculino , Metaboloma/genética , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico/genética
11.
Hum Genet ; 135(3): 273-85, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26742502

RESUMO

The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS; MIM #192430; 188400) is the most common microdeletion syndrome. The phenotypic presentation of 22q11DS is highly variable; approximately 60-75 % of 22q11DS patients have been reported to have a congenital heart defect (CHD), mostly of the conotruncal type, and/or aortic arch defect. The etiology of the cardiac phenotypic variability is not currently known for the majority of patients. We hypothesized that rare copy number variants (CNVs) outside the 22q11.2 deleted region may modify the risk of being born with a CHD in this sensitized population. Rare CNV analysis was performed using Affymetrix SNP Array 6.0 data from 946 22q11DS subjects with CHDs (n = 607) or with normal cardiac anatomy (n = 339). Although there was no significant difference in the overall burden of rare CNVs, an overabundance of CNVs affecting cardiac-related genes was detected in 22q11DS individuals with CHDs. When the rare CNVs were examined with regard to gene interactions, specific cardiac networks, such as Wnt signaling, appear to be overrepresented in 22q11DS CHD cases but not 22q11DS controls with a normal heart. Collectively, these data suggest that CNVs outside the 22q11.2 region may contain genes that modify risk for CHDs in some 22q11DS patients.


Assuntos
Variações do Número de Cópias de DNA , Síndrome de DiGeorge/genética , Cardiopatias Congênitas/genética , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/diagnóstico , Técnicas de Genotipagem , Cardiopatias Congênitas/diagnóstico , Humanos
12.
J Gen Virol ; 97(1): 209-19, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26489905

RESUMO

During virus assembly, HIV-1 Gag-Pol is packaged into virions via interaction with Pr55gag. Studies suggest that Gag-Pol by itself is incapable of virus particle assembly or cell release, perhaps due to the lack of a budding domain in the form of p6gag, which is truncated within Gag-Pol because of a ribosomal frameshift during Gag translation. Additionally (or alternatively), large molecular size may not support Gag-Pol assembly into virus-like particles (VLPs) or release from cells. To test these hypotheses, we constructed Gag-Pol expression vectors retaining and lacking p6gag, and then reduced Gag-Pol molecular size by removing various lengths of the Pol sequence. Results indicate that Gag-Pol constructs retaining p6gag were capable of forming VLPs with a WT HIV-1 particle density. Gag-Pol molecular size reduction via partial removal of the Pol sequence mitigated the Gag-Pol assembly defect to a moderate degree. Our results suggest that the Gag-Pol assembly and budding defects are largely due to a lack of p6gag, but also in part due to size limitation.


Assuntos
HIV-1/fisiologia , Montagem de Vírus , Liberação de Vírus , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Análise Mutacional de DNA , HIV-1/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
13.
Am J Hum Genet ; 97(6): 869-77, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26608785

RESUMO

We performed whole exome sequence (WES) to identify genetic modifiers on 184 individuals with 22q11.2 deletion syndrome (22q11DS), of whom 89 case subjects had severe congenital heart disease (CHD) and 95 control subjects had normal hearts. Three genes including JMJD1C (jumonji domain containing 1C), RREB1 (Ras responsive element binding protein 1), and SEC24C (SEC24 family member C) had rare (MAF < 0.001) predicted deleterious single-nucleotide variations (rdSNVs) in seven case subjects and no control subjects (p = 0.005; Fisher exact and permutation tests). Because JMJD1C and RREB1 are involved in chromatin modification, we investigated other histone modification genes. Eighteen case subjects (20%) had rdSNVs in four genes (JMJD1C, RREB1, MINA, KDM7A) all involved in demethylation of histones (H3K9, H3K27). Overall, rdSNVs were enriched in histone modifier genes that activate transcription (Fisher exact p = 0.0004, permutations, p = 0.0003, OR = 5.16); however, rdSNVs in control subjects were not enriched. This implicates histone modification genes as influencing risk for CHD in presence of the deletion.


Assuntos
Proteínas de Ligação a DNA/genética , Síndrome de DiGeorge/genética , Cardiopatias Congênitas/genética , Histonas/genética , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas Nucleares/genética , Oxirredutases N-Desmetilantes/genética , Fatores de Transcrição/genética , Estudos de Casos e Controles , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/patologia , Exoma , Regulação da Expressão Gênica , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Histonas/metabolismo , Humanos , Anotação de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único , Risco , Transcrição Genética , Proteínas de Transporte Vesicular/genética
14.
Am J Hum Genet ; 96(5): 753-64, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25892112

RESUMO

The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS) is the most common microdeletion syndrome and the phenotypic presentation is highly variable. Approximately 65% of individuals with 22q11DS have a congenital heart defect (CHD), mostly of the conotruncal type, and/or an aortic arch defect. The etiology of this phenotypic variability is not currently known. We hypothesized that copy-number variants (CNVs) outside the 22q11.2 deleted region might increase the risk of being born with a CHD in this sensitized population. Genotyping with Affymetrix SNP Array 6.0 was performed on two groups of subjects with 22q11DS separated by time of ascertainment and processing. CNV analysis was completed on a total of 949 subjects (cohort 1, n = 562; cohort 2, n = 387), 603 with CHDs (cohort 1, n = 363; cohort 2, n = 240) and 346 with normal cardiac anatomy (cohort 1, n = 199; cohort 2, n = 147). Our analysis revealed that a duplication of SLC2A3 was the most frequent CNV identified in the first cohort. It was present in 18 subjects with CHDs and 1 subject without (p = 3.12 × 10(-3), two-tailed Fisher's exact test). In the second cohort, the SLC2A3 duplication was also significantly enriched in subjects with CHDs (p = 3.30 × 10(-2), two-tailed Fisher's exact test). The SLC2A3 duplication was the most frequent CNV detected and the only significant finding in our combined analysis (p = 2.68 × 10(-4), two-tailed Fisher's exact test), indicating that the SLC2A3 duplication might serve as a genetic modifier of CHDs and/or aortic arch anomalies in individuals with 22q11DS.


Assuntos
Variações do Número de Cópias de DNA/genética , Síndrome de DiGeorge/genética , Transportador de Glucose Tipo 3/genética , Cardiopatias Congênitas/genética , Adulto , Aorta Torácica/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Feminino , Genótipo , Cardiopatias Congênitas/fisiopatologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
15.
Biomed Res Int ; 2014: 236702, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24790992

RESUMO

BACKGROUND: Several common single-nucleotide polymorphisms (SNPs) at apolipoprotein E (ApoE) have been linked with late onset sporadic Alzheimer's disease and declining normative cognitive ability in elder people, but we are unclear about their relationship with cognition in children. RESULTS: We studied -491A/T, -427T/C, and -219G/T promoter polymorphisms and ε2/ε3/ε4 at ApoE among children with mental retardation (MR, n = 130), borderline MR (n = 124), and controls (n = 334) from an iodine deficiency area in China. The allelic and genotypic distribution of individual locus did not significantly differ among three groups with Mantel-Haenszel χ (2) test (P > 0.05). However, frequencies of haplotype of -491A/-427T/-219T/ε4 were distributed as MR > borderline MR > controls (P uncorrected = 0.004), indicating that the presence of this haplotype may increase the risk of disease. CONCLUSIONS: In this large population-based study in children, we did not find any significant association between single locus of the four common ApoE polymorphisms (-491A/T, -427T/C, -219T/G, and ε2/3/4) and MR or borderline MR. However, we found that the presence of ATTε4 haplotype was associated with an increased risk of MR and borderline MR. Our present work may help enlarge our knowledge of the cognitive role of ApoE across the lifespan and the mechanisms of human cognition.


Assuntos
Apolipoproteínas E/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Deficiência Intelectual/genética , Iodo/deficiência , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Sequência de Bases , Criança , China/epidemiologia , Comorbidade , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Humanos , Incidência , Masculino , Dados de Sequência Molecular , Fatores de Risco
16.
Hum Mol Genet ; 23(16): 4215-31, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24705356

RESUMO

Velo-cardio-facial/DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a congenital anomaly disorder characterized by craniofacial anomalies including velo-pharyngeal insufficiency, facial muscle hypotonia and feeding difficulties, in part due to hypoplasia of the branchiomeric muscles. Inactivation of both alleles of mouse Tbx1, encoding a T-box transcription factor, deleted on chromosome 22q11.2, results in reduction or loss of branchiomeric muscles. To identify downstream pathways, we performed gene profiling of microdissected pharyngeal arch one (PA1) from Tbx1(+/+) and Tbx1(-/-) embryos at stages E9.5 (somites 20-25) and E10.5 (somites 30-35). Basic helix-loop-helix (bHLH) transcription factors were reduced, while secondary heart field genes were increased in expression early and were replaced by an increase in expression of cellular stress response genes later, suggesting a change in gene expression patterns or cell populations. Lineage tracing studies using Mesp1(Cre) and T-Cre drivers showed that core mesoderm cells within PA1 were present at E9.5 but were greatly reduced by E10.5 in Tbx1(-/-) embryos. Using Tbx1(Cre) knock-in mice, we found that cells are lost due to apoptosis, consistent with increase in expression of cellular stress response genes at E10.5. To determine whether Tbx1 is required autonomously in the core mesoderm, we used Mesp1(Cre) and T-Cre mesodermal drivers in combination with inactivate Tbx1 and found reduction or loss of branchiomeric muscles from PA1. These mechanistic studies inform us that Tbx1 is required upstream of key myogenic genes needed for core mesoderm cell survival and fate, between E9.5 and E10.5, resulting in formation of the branchiomeric muscles.


Assuntos
Diferenciação Celular/genética , Mastigação/genética , Músculos/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Animais , Apoptose/genética , Sobrevivência Celular/genética , Desenvolvimento Embrionário/genética , Mesoderma/metabolismo , Camundongos , Camundongos Knockout , Faringe/metabolismo
17.
Genet Epidemiol ; 38(2): 162-71, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24446417

RESUMO

Genome-wide association studies (GWAS) offer an excellent opportunity to identify the genetic variants underlying complex human diseases. Successful utilization of this approach requires a large sample size to identify single nucleotide polymorphisms (SNPs) with subtle effects. Meta-analysis is a cost-efficient means to achieve large sample size by combining data from multiple independent GWAS; however, results from studies performed on different populations can be variable due to various reasons, including varied linkage equilibrium structures as well as gene-gene and gene-environment interactions. Nevertheless, one should expect effects of the SNP are more similar between similar populations than those between populations with quite different genetic and environmental backgrounds. Prior information on populations of GWAS is often not considered in current meta-analysis methods, rendering such analyses less optimal for the detecting association. This article describes a test that improves meta-analysis to incorporate variable heterogeneity among populations. The proposed method is remarkably simple in computation and hence can be performed in a rapid fashion in the setting of GWAS. Simulation results demonstrate the validity and higher power of the proposed method over conventional methods in the presence of heterogeneity. As a demonstration, we applied the test to real GWAS data to identify SNPs associated with circulating insulin-like growth factor I concentrations.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Fator de Crescimento Insulin-Like I/metabolismo , Metanálise como Assunto , Simulação por Computador , Ligação Genética , Genoma , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Tamanho da Amostra
18.
Diabetes ; 63(1): 369-76, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24101674

RESUMO

Most genetic variants associated with type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWASs) in Europeans. The current study reports a GWAS for young-onset T2DM in American Indians. Participants were selected from a longitudinal study conducted in Pima Indians and included 278 cases with diabetes with onset before 25 years of age, 295 nondiabetic controls ≥45 years of age, and 267 siblings of cases or controls. Individuals were genotyped on a ∼1M single nucleotide polymorphism (SNP) array, resulting in 453,654 SNPs with minor allele frequency >0.05. SNPs were analyzed for association in cases and controls, and a family-based association test was conducted. Tag SNPs (n = 311) were selected for 499 SNPs associated with diabetes (P < 0.0005 in case-control analyses or P < 0.0003 in family-based analyses), and these SNPs were genotyped in up to 6,834 additional Pima Indians to assess replication. Rs1861612 in DNER was associated with T2DM (odds ratio = 1.29 per copy of the T allele; P = 6.6 × 10(-8), which represents genome-wide significance accounting for the number of effectively independent SNPs analyzed). Transfection studies in murine pancreatic ß-cells suggested that DNER regulates expression of notch signaling pathway genes. These studies implicate DNER as a susceptibility gene for T2DM in American Indians.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Índios Norte-Americanos/genética , Proteínas do Tecido Nervoso/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Idoso , Alelos , Diabetes Mellitus Tipo 2/etnologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
19.
Diabetes ; 62(8): 2984-91, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23630301

RESUMO

Parent-of-origin effects were observed in an Icelandic population for several genetic variants associated with type 2 diabetes, including those in KLF14 (rs4731702), MOB2 (rs2334499), and KCNQ1 (rs2237892, rs231362). We analyzed parent-of-origin effects for these variants, along with two others in KCNQ1 identified in previous genome-wide association studies (rs2237895, rs2299620), in 7,351 Pima Indians from 4,549 nuclear families; 34% of participants had diabetes. In a subset of 287 normoglycemic individuals, acute insulin secretion was measured by an intravenous glucose tolerance test. Statistically significant (P < 0.05) parent-of-origin effects were seen for association with type 2 diabetes for all variants. The strongest effect was seen at rs2299620 in KCNQ1; the C allele was associated with increased diabetes when maternally derived (odds ratio [OR], 1.92; P = 4.1 × 10(-12)), but not when paternally derived (OR, 0.93; P = 0.47; P = 9.9 × 10(-6) for difference in maternal and paternal effects). A maternally derived C allele also was associated with a 28% decrease in insulin secretion (P = 0.002). This study confirms parent-of-origin effects in the association with type 2 diabetes for variants in KLF14, MOB2, and KCNQ1. In Pima Indians, the effect of maternally derived KCNQ1 variants appears to be mediated through decreased insulin secretion and is particularly strong, accounting for 4% of the variance in liability to diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Índios Norte-Americanos/genética , Canal de Potássio KCNQ1/genética , Adulto , Alelos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Teste de Tolerância a Glucose , Haplótipos , Humanos , Insulina/genética , Insulina/metabolismo , Estudos Longitudinais , Masculino , Proteínas do Tecido Nervoso/genética , Pais , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição Sp/genética
20.
Am J Hum Genet ; 92(3): 439-47, 2013 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-23453669

RESUMO

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22 , Síndrome de DiGeorge/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino
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