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1.
Am J Med Genet A ; 185(3): 916-922, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33369125

RESUMO

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss-of-function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4-related EPF phenotype. This report demonstrates comorbid disorders of Saethre-Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification.

2.
J Clin Invest ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001864

RESUMO

BACKGROUND: Transcriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq guided method to diagnose individuals across a wide range of ages and clinical phenotypes. METHODS: One hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network (UDN) clinical site from 2014-2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis. RESULTS: The transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts. CONCLUSION: For our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA.

3.
Nat Commun ; 11(1): 2441, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415109

RESUMO

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.


Assuntos
Cinesina/genética , Atividade Motora , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Animais , Axônios/metabolismo , Movimento Celular , Proliferação de Células , Córtex Cerebral/embriologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Masculino , Camundongos , Mutação de Sentido Incorreto/genética , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Neurônios/metabolismo , Tamanho do Órgão , Organogênese/genética , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/genética
4.
Am J Med Genet A ; 182(6): 1387-1399, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32233023

RESUMO

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population. METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW. RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023). CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

5.
Genet Med ; 21(11): 2453-2461, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30992551

RESUMO

PURPOSE: Maternal diabetes is a known teratogen that can cause a wide spectrum of birth defects, collectively referred to as diabetic embryopathy (DE). However, the pathogenic mechanisms underlying DE remain uncertain and there are no definitive tests to establish the diagnosis. Here, we explore the potential of DNA methylation as a diagnostic biomarker for DE and to inform disease pathogenesis. METHODS: Bisulfite sequencing was used to identify gene regions with differential methylation between DE neonates and healthy infants born with or without prenatal exposure to maternal diabetes, and to investigate the role of allele-specific methylation at implicated sites. RESULTS: We identified a methylation signature consisting of 237 differentially methylated loci that distinguished infants with DE from control infants. These loci were found proximal to genes associated with Mendelian syndromes that overlap the DE phenotype (e.g., CACNA1C, TRIO, ANKRD11) or genes known to influence embryonic development (e.g., BRAX1, RASA3). Further, we identified allele-specific methylation (ASM) at 11 of these loci, within which 61.5% of ASM single-nucleotide variants are known expression quantitative trait loci (eQTLs). CONCLUSIONS: Our study suggests a role for aberrant DNA methylation and cis-sequence variation in the pathogenesis of DE and highlights the diagnostic potential of DNA methylation for teratogenic birth defects.


Assuntos
Metilação de DNA/genética , Diabetes Mellitus/embriologia , Doenças Fetais/genética , Alelos , Biomarcadores , Ilhas de CpG/genética , Complicações do Diabetes/genética , Diabetes Mellitus/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Locos de Características Quantitativas/genética
6.
Clin Epigenetics ; 11(1): 60, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961659

RESUMO

BACKGROUND: Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants. RESULTS: To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite sequencing of chromosome 16 on peripheral blood and cultured skin fibroblasts from individuals with maternal or paternal upd(16) as well as lung tissue from patients with ACDMPV-causative 16q24.1 deletions and a normal control. We identified 22 differentially methylated regions (DMRs) with ≥ 5 consecutive CpG methylation sites and varying tissue-specificity, including the known DMRs associated with the established imprinted gene ZNF597 and DMRs supporting maternal methylation of PRR25, thought to be paternally expressed in lymphoblastoid cells. Lastly, we found evidence of paternal methylation on 16q24.1 near LINC01082 mapping to the FOXF1 enhancer. CONCLUSIONS: Using high-resolution bisulfite sequencing to evaluate DNA methylation across chromosome 16, we found evidence for novel candidate imprinted loci on chromosome 16 that would not be evident in array-based assays and could contribute to the birth defects observed in patients with upd(16)mat or in ACDMPV.


Assuntos
Metilação de DNA , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Dissomia Uniparental/genética , Células Cultivadas , Cromossomos Humanos Par 16/genética , Feminino , Fibroblastos/química , Fibroblastos/citologia , Impressão Genômica , Humanos , Masculino , Pele/química , Pele/citologia
8.
Brain Struct Funct ; 223(6): 2733-2751, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29574585

RESUMO

The acoustic startle reflex (ASR) is a short and intense defensive reaction in response to a loud and unexpected acoustic stimulus. In the rat, a primary startle pathway encompasses three serially connected central structures: the cochlear root neurons, the giant neurons of the nucleus reticularis pontis caudalis (PnC), and the spinal motoneurons. As a sensorimotor interface, the PnC has a central role in the ASR circuitry, especially the integration of different sensory stimuli and brain states into initiation of motor responses. Since the basal ganglia circuits control movement and action selection, we hypothesize that their output via the substantia nigra (SN) may interplay with the ASR primary circuit by providing inputs to PnC. Moreover, the pedunculopontine tegmental nucleus (PPTg) has been proposed as a functional and neural extension of the SN, so it is another goal of this study to describe possible anatomical connections from the PPTg to PnC. Here, we made 6-OHDA neurotoxic lesions of the SN pars compacta (SNc) and submitted the rats to a custom-built ASR measurement session to assess amplitude and latency of motor responses. We found that following lesion of the SNc, ASR amplitude decreased and latency increased compared to those values from the sham-surgery and control groups. The number of dopamine neurons remaining in the SNc after lesion was also estimated using a stereological approach, and it correlated with our behavioral results. Moreover, we employed neural tract-tracing techniques to highlight direct projections from the SN to PnC, and indirect projections through the PPTg. Finally, we also measured levels of excitatory amino acid neurotransmitters in the PnC following lesion of the SN, and found that they change following an ipsi/contralateral pattern. Taken together, our results identify nigrofugal efferents onto the primary ASR circuit that may modulate motor responses.


Assuntos
Vias Auditivas/fisiologia , Movimento/fisiologia , Reflexo de Sobressalto/fisiologia , Formação Reticular/fisiologia , Substância Negra/fisiologia , Estimulação Acústica , Animais , Vias Auditivas/efeitos dos fármacos , Biotina/análogos & derivados , Biotina/metabolismo , Conectoma , Dextranos/metabolismo , Lateralidade Funcional/efeitos dos fármacos , Masculino , NADPH Desidrogenase/metabolismo , Neurotoxinas/toxicidade , Neurotransmissores/metabolismo , Oxidopamina/toxicidade , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Reflexo de Sobressalto/efeitos dos fármacos , Formação Reticular/efeitos dos fármacos , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Estilbamidinas/metabolismo , Substância Negra/lesões , Tirosina 3-Mono-Oxigenase/metabolismo
9.
Am J Med Genet A ; 173(8): 2176-2188, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28653806

RESUMO

Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals.


Assuntos
Variações do Número de Cópias de DNA/genética , Cardiopatias Congênitas/genética , Coração/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genômica , Genótipo , Cardiopatias Congênitas/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
11.
Hum Mol Genet ; 25(11): 2331-2341, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26965164

RESUMO

Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 × 10-8 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 × 10-9, odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 × 10-5, OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 × 10-9 for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 × 10-7 for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high ([Formula: see text] range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.


Assuntos
Cromossomos Humanos Par 20/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias Congênitas/genética , Mapeamento Cromossômico , Estudos de Coortes , Feminino , Genótipo , Cardiopatias Congênitas/fisiopatologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
12.
Am J Hum Genet ; 98(2): 347-57, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26805781

RESUMO

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.


Assuntos
Arritmias Cardíacas/genética , Debilidade Muscular/genética , Rabdomiólise/genética , Alelos , Árabes/genética , Arritmias Cardíacas/diagnóstico , Sequência de Bases , Criança , Pré-Escolar , Estresse do Retículo Endoplasmático/genética , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Éxons , Feminino , Deleção de Genes , Complexo de Golgi/genética , Complexo de Golgi/metabolismo , Hispano-Americanos/genética , Homozigoto , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Debilidade Muscular/diagnóstico , Linhagem , Rabdomiólise/diagnóstico
13.
Am J Hum Genet ; 97(6): 904-13, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26637980

RESUMO

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.


Assuntos
Microtia Congênita/genética , Nanismo/genética , Geminina/genética , Transtornos do Crescimento/genética , Micrognatismo/genética , Mutação , Patela/anormalidades , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Ciclo Celular/genética , Pré-Escolar , Microtia Congênita/metabolismo , Nanismo/metabolismo , Nanismo/patologia , Éxons , Feminino , Geminina/metabolismo , Expressão Gênica , Genes Dominantes , Transtornos do Crescimento/metabolismo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Padrões de Herança , Masculino , Micrognatismo/metabolismo , Dados de Sequência Molecular , Patela/metabolismo , Linhagem , Estabilidade Proteica , Proteólise , Processamento de RNA , Alinhamento de Sequência
14.
PLoS Pathog ; 11(6): e1004869, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26070066

RESUMO

To better understand the systemic response to naturally acquired acute respiratory viral infections, we prospectively enrolled 1610 healthy adults in 2009 and 2010. Of these, 142 subjects were followed for detailed evaluation of acute viral respiratory illness. We examined peripheral blood gene expression at 7 timepoints: enrollment, 5 illness visits and the end of each year of the study. 133 completed all study visits and yielded technically adequate peripheral blood microarray gene expression data. Seventy-three (55%) had an influenza virus infection, 64 influenza A and 9 influenza B. The remaining subjects had a rhinovirus infection (N = 32), other viral infections (N = 4), or no viral agent identified (N = 24). The results, which were replicated between two seasons, showed a dramatic upregulation of interferon pathway and innate immunity genes. This persisted for 2-4 days. The data show a recovery phase at days 4 and 6 with differentially expressed transcripts implicated in cell proliferation and repair. By day 21 the gene expression pattern was indistinguishable from baseline (enrollment). Influenza virus infection induced a higher magnitude and longer duration of the shared expression signature of illness compared to the other viral infections. Using lineage and activation state-specific transcripts to produce cell composition scores, patterns of B and T lymphocyte depressions accompanied by a major activation of NK cells were detected in the acute phase of illness. The data also demonstrate multiple dynamic gene modules that are reorganized and strengthened following infection. Finally, we examined pre- and post-infection anti-influenza antibody titers defining novel gene expression correlates.


Assuntos
Influenza Humana/genética , Influenza Humana/imunologia , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Adolescente , Adulto , Estudos de Coortes , Resfriado Comum/genética , Resfriado Comum/imunologia , Feminino , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza B/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Rhinovirus/imunologia , Transcrição Genética , Transcriptoma , Adulto Jovem
15.
Elife ; 2: e00299, 2013 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-23878721

RESUMO

Identification of the host genetic factors that contribute to variation in vaccine responsiveness may uncover important mechanisms affecting vaccine efficacy. We carried out an integrative, longitudinal study combining genetic, transcriptional, and immunologic data in humans given seasonal influenza vaccine. We identified 20 genes exhibiting a transcriptional response to vaccination, significant genotype effects on gene expression, and correlation between the transcriptional and antibody responses. The results show that variation at the level of genes involved in membrane trafficking and antigen processing significantly influences the human response to influenza vaccination. More broadly, we demonstrate that an integrative study design is an efficient alternative to existing methods for the identification of genes involved in complex traits. DOI:http://dx.doi.org/10.7554/eLife.00299.001.


Assuntos
Genômica , Imunidade Humoral/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/genética , Influenza Humana/prevenção & controle , Vacinação , Adolescente , Adulto , Anticorpos Antivirais/sangue , Biomarcadores/sangue , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Marcadores Genéticos , Genômica/métodos , Genótipo , Interações Hospedeiro-Patógeno , Humanos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Influenza Humana/virologia , Estudos Longitudinais , Masculino , Farmacogenética , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Tempo , Transcrição Genética , Adulto Jovem
16.
Am J Hum Genet ; 93(2): 197-210, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23810381

RESUMO

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.


Assuntos
Senilidade Prematura/genética , Sequência de Bases , Predisposição Genética para Doença , Transtornos do Desenvolvimento da Linguagem/genética , Leucoencefalopatias/genética , Deleção de Sequência , Tetraspaninas/genética , Idade de Início , Senilidade Prematura/complicações , Senilidade Prematura/etnologia , Senilidade Prematura/patologia , Grupo com Ancestrais do Continente Asiático , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 2 , Éxons , Feminino , Humanos , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/etnologia , Transtornos do Desenvolvimento da Linguagem/patologia , Leucoencefalopatias/complicações , Leucoencefalopatias/etnologia , Leucoencefalopatias/patologia , Imagem por Ressonância Magnética , Masculino , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNA
17.
Hum Mol Genet ; 22(21): 4339-48, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23773997

RESUMO

Coarctation of the aorta (CoA) and hypoplastic left heart syndrome (HLHS) have been reported in rare individuals with large terminal deletions of chromosome 15q26. However, no single gene important for left ventricular outflow tract (LVOT) development has been identified in this region. Using array-comparative genomic hybridization, we identified two half-siblings with CoA with a 2.2 Mb deletion on 15q26.2, inherited from their mother, who was mosaic for this deletion. This interval contains an evolutionary conserved, protein-coding gene, MCTP2 (multiple C2-domains with two transmembrane regions 2). Using gene-specific array screening in 146 individuals with non-syndromic LVOT obstructive defects, another individual with HLHS and CoA was found to have a de novo 41 kb intragenic duplication within MCTP2, predicted to result in premature truncation, p.F697X. Alteration of Mctp2 gene expression in Xenopus laevis embryos by morpholino knockdown and mRNA overexpression resulted in the failure of proper OT development, confirming the functional importance of this dosage-sensitive gene for cardiogenesis. Our results identify MCTP2 as a novel genetic cause of CoA and related cardiac malformations.


Assuntos
Coartação Aórtica/genética , Ventrículos do Coração/crescimento & desenvolvimento , Síndrome do Coração Esquerdo Hipoplásico/genética , Proteínas de Membrana/genética , Animais , Hibridização Genômica Comparativa , Feminino , Dosagem de Genes , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Variação Genética , Humanos , Síndrome do Coração Esquerdo Hipoplásico/etnologia , Masculino , Modelos Animais , Análise de Sequência de DNA , Deleção de Sequência , Xenopus laevis/embriologia , Xenopus laevis/genética , Xenopus laevis/crescimento & desenvolvimento
18.
Birth Defects Res A Clin Mol Teratol ; 91(3): 162-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21290564

RESUMO

BACKGROUND: The left ventricular outflow tract (LVOT) defects aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS) represent an embryologically related group of congenital cardiovascular malformations. They are common and cause substantial morbidity and mortality. Prior evidence suggests a strong genetic component in their causation. METHODS: We selected NRG1, ERBB3, and ERBB4 of the epidermal growth factor receptor (EGFR) signaling pathway as candidate genes for investigation of association with LVOT defects based on the importance of this pathway in cardiac development and the phenotypes in knockout mouse models. Single nucleotide polymorphism (SNP) genotyping was performed on 343 affected case-parent trios of European ancestry. RESULTS: We identified a specific haplotype in intron 3 of ERBB4 that was positively associated with the combined LVOT defects phenotype (p=0.0005) and in each anatomic defect AVS, COA, and HLHS separately. Mutation screening of individuals with an LVOT defect failed to identify a coding sequence or splice site change in ERBB4. RT-PCR on lymphoblastoid cells from LVOT subjects did not show altered splice variant ratios among those homozygous for the associated haplotype. CONCLUSION: These results suggest ERBB4 is associated with LVOT defects. Further replication will be required in separate cohorts to confirm the consistency of the observed association.


Assuntos
Receptores ErbB/genética , Polimorfismo de Nucleotídeo Único , Obstrução do Fluxo Ventricular Externo/congênito , Obstrução do Fluxo Ventricular Externo/genética , Criança , Estudos de Coortes , Feminino , Frequência do Gene , Genes erbB/genética , Ligação Genética , Predisposição Genética para Doença , Genótipo , Cardiopatias Congênitas/genética , Humanos , Masculino , Neuregulina-1/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Isoformas de Proteínas/genética , Receptor ErbB-4
19.
PLoS Genet ; 2(12): e215, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17194221

RESUMO

Ongoing modernization in India has elevated the prevalence of many complex genetic diseases associated with a western lifestyle and diet to near-epidemic proportions. However, although India comprises more than one sixth of the world's human population, it has largely been omitted from genomic surveys that provide the backdrop for association studies of genetic disease. Here, by genotyping India-born individuals sampled in the United States, we carry out an extensive study of Indian genetic variation. We analyze 1,200 genome-wide polymorphisms in 432 individuals from 15 Indian populations. We find that populations from India, and populations from South Asia more generally, constitute one of the major human subgroups with increased similarity of genetic ancestry. However, only a relatively small amount of genetic differentiation exists among the Indian populations. Although caution is warranted due to the fact that United States-sampled Indian populations do not represent a random sample from India, these results suggest that the frequencies of many genetic variants are distinctive in India compared to other parts of the world and that the effects of population heterogeneity on the production of false positives in association studies may be smaller in Indians (and particularly in Indian-Americans) than might be expected for such a geographically and linguistically diverse subset of the human population.


Assuntos
Alelos , Frequência do Gene , Variação Genética , Idioma , Análise por Conglomerados , Elementos de DNA Transponíveis/genética , Europa (Continente) , Extremo Oriente , Deleção de Genes , Humanos , Índia/etnologia , Repetições de Microssatélites/genética , Oriente Médio , Polimorfismo Genético , Software
20.
Eur J Pharmacol ; 445(1-2): 87-91, 2002 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-12065198

RESUMO

The effects of acamprosate, a drug thought to interact with N-methyl-D-aspartate (NMDA) receptors in the central nervous system (CNS), were examined on the antinociceptive action of morphine, induction of tolerance to and physical dependence on morphine, and expression of the abstinence syndrome to the opiate in mice. For the induction of tolerance and dependence, morphine (300 mg/kg) was administered by means of a slow-release preparation. Single doses of acamprosate (50, 100, 200, or 400 mg/kg) administered 30 min before a test dose of morphine did not change the antinociceptive effects of morphine in drug-naive mice. The drug was also administered in repeated doses (50, 100, 200, or 400 mg/kg, 30 min before and 12 and 24 h after the priming dose of morphine) in order to evaluate its effects on the induction of tolerance; all doses assayed, except the 400 mg/kg, did not affect the intensity of tolerance. The acute administration of acamprosate (50, 100, 200, or 400 mg/kg, injected 30 min before naloxone to morphine-pretreated mice) did not affect the intensity of the abstinence behavior. However, the repeated administration of 100 mg/kg of acamprosate (30 min before and 12 and 24 h after the priming dose of morphine) decreased the intensity of physical dependence. The results of these studies suggest that acamprosate may have modulatory effects on glutamatergic neurotransmission participating in the adaptive mechanisms induced by chronic morphine treatment.


Assuntos
Tolerância a Medicamentos/fisiologia , Dependência de Morfina/tratamento farmacológico , Morfina/efeitos adversos , Taurina/análogos & derivados , Taurina/uso terapêutico , Acamprosato , Animais , Masculino , Camundongos , Morfina/farmacologia , Dependência de Morfina/fisiopatologia , Medição da Dor/efeitos dos fármacos , Taurina/farmacologia
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