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1.
Circulation ; 146(23): 1758-1778, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36259389

RESUMO

BACKGROUND: Phosphodiesterase 3A (PDE3A) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertrophy or heart failure. We hypothesized that, in the heart, PDE3A mutations could be protective. METHODS: We studied new patients. CRISPR-Cas9-engineered rat HTNB models were phenotyped by telemetric blood pressure measurements, echocardiography, microcomputed tomography, RNA-sequencing, and single nuclei RNA-sequencing. Human induced pluripotent stem cells carrying PDE3A mutations were established, differentiated to cardiomyocytes, and analyzed by Ca2+ imaging. We used Förster resonance energy transfer and biochemical assays. RESULTS: We identified a new PDE3A mutation in a family with HTNB. It maps to exon 13 encoding the enzyme's catalytic domain. All hitherto identified HTNB PDE3A mutations cluster in exon 4 encoding a region N-terminally from the catalytic domain of the enzyme. The mutations were recapitulated in rat models. Both exon 4 and 13 mutations led to aberrant phosphorylation, hyperactivity, and increased PDE3A enzyme self-assembly. The left ventricles of our patients with HTNB and the rat models were normal despite preexisting hypertension. A catecholamine challenge elicited cardiac hypertrophy in HTNB rats only to the level of wild-type rats and improved the contractility of the mutant hearts, compared with wild-type rats. The ß-adrenergic system, phosphodiesterase activity, and cAMP levels in the mutant hearts resembled wild-type hearts, whereas phospholamban phosphorylation was decreased in the mutants. In our induced pluripotent stem cell cardiomyocyte models, the PDE3A mutations caused adaptive changes of Ca2+ cycling. RNA-sequencing and single nuclei RNA-sequencing identified differences in mRNA expression between wild-type and mutants, affecting, among others, metabolism and protein folding. CONCLUSIONS: Although in vascular smooth muscle, PDE3A mutations cause hypertension, they confer protection against hypertension-induced cardiac damage in hearts. Nonselective PDE3A inhibition is a final, short-term option in heart failure treatment to increase cardiac cAMP and improve contractility. Our data argue that mimicking the effect of PDE3A mutations in the heart rather than nonselective PDE3 inhibition is cardioprotective in the long term. Our findings could facilitate the search for new treatments to prevent hypertension-induced cardiac damage.


Assuntos
Insuficiência Cardíaca , Hipertensão , Células-Tronco Pluripotentes Induzidas , Humanos , Ratos , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Microtomografia por Raio-X , Células-Tronco Pluripotentes Induzidas/metabolismo , Hipertensão/complicações , Hipertensão/genética , Miócitos Cardíacos/metabolismo , Cardiomegalia , RNA
2.
EMBO J ; 37(15)2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29921581

RESUMO

Chromosomes occupy distinct interphase territories in the three-dimensional nucleus. However, how these chromosome territories are arranged relative to one another is poorly understood. Here, we investigated the inter-chromosomal interactions between chromosomes 2q, 12, and 17 in human mesenchymal stem cells (MSCs) and MSC-derived cell types by DNA-FISH We compared our findings in normal karyotypes with a three-generation family harboring a 2q37-deletion syndrome, featuring a heterozygous partial deletion of histone deacetylase 4 (HDAC4) on chr2q37. In normal karyotypes, we detected stable, recurring arrangements and interactions between the three chromosomal territories with a tissue-specific interaction bias at certain loci. These inter-chromosomal interactions were confirmed by Hi-C. Interestingly, the disease-related HDAC4 deletion resulted in displaced inter-chromosomal arrangements and altered interactions between the deletion-affected chromosome 2 and chromosome 12 and/or 17 in 2q37-deletion syndrome patients. Our findings provide evidence for a direct link between a structural chromosomal aberration and altered interphase architecture that results in a nuclear configuration, supporting a possible molecular pathogenesis.


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 2/genética , Deleção de Genes , Histona Desacetilases/genética , Proteínas Repressoras/genética , Translocação Genética/genética , Núcleo Celular/genética , Deleção Cromossômica , Humanos , Hibridização in Situ Fluorescente , Interfase/genética , Células-Tronco Mesenquimais/citologia
3.
Circulation ; 142(2): 133-149, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32524868

RESUMO

BACKGROUND: High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal dominant hypertension with brachydactyly clinically resembles salt-resistant essential hypertension and causes death by stroke before 50 years of age. We recently implicated the gene encoding phosphodiesterase 3A (PDE3A); however, in vivo modeling of the genetic defect and thus showing an involvement of mutant PDE3A is lacking. METHODS: We used genetic mapping, sequencing, transgenic technology, CRISPR-Cas9 gene editing, immunoblotting, and fluorescence resonance energy transfer. We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways. RESULTS: We describe a novel mutation within a 15 base pair (bp) region of the PDE3A gene and define this segment as a mutational hotspot in hypertension with brachydactyly. The mutations cause an increase in enzyme activity. A CRISPR/Cas9-generated rat model, with a 9-bp deletion within the hotspot analogous to a human deletion, recapitulates hypertension with brachydactyly. In mice, mutant transgenic PDE3A overexpression in smooth muscle cells confirmed that mutant PDE3A causes hypertension. The mutant PDE3A enzymes display consistent changes in their phosphorylation and an increased interaction with the 14-3-3θ adaptor protein. This aberrant signaling is associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function. CONCLUSIONS: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance causing hypertension. We present 2 new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Hipertensão/genética , Mutação , Alelos , Substituição de Aminoácidos , Animais , Animais Geneticamente Modificados , Pressão Arterial , Biomarcadores/sangue , Biomarcadores/urina , Braquidactilia/diagnóstico , Braquidactilia/genética , Sistemas CRISPR-Cas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Análise Mutacional de DNA , Modelos Animais de Doenças , Ativação Enzimática , Marcação de Genes , Estudos de Associação Genética/métodos , Genótipo , Imuno-Histoquímica , Isoenzimas , Masculino , Linhagem , Fenótipo , Radiografia , Ratos , Sistema Renina-Angiotensina/genética
5.
Life Sci Alliance ; 7(4)2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38331475

RESUMO

Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64-65. ADAM-19 cleavage increased Gq and decreased Gs activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions.


Assuntos
Braquidactilia , Proteína Relacionada ao Hormônio Paratireóideo , Humanos , Proteína Relacionada ao Hormônio Paratireóideo/genética , Braquidactilia/genética , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Metaloproteases , Proteínas ADAM
6.
Hum Mol Genet ; 19(5): 848-60, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20015959

RESUMO

Parathyroid hormone-like hormone (PTHLH) is an important chondrogenic regulator; however, the gene has not been directly linked to human disease. We studied a family with autosomal-dominant Brachydactyly Type E (BDE) and identified a t(8;12)(q13;p11.2) translocation with breakpoints (BPs) upstream of PTHLH on chromosome 12p11.2 and a disrupted KCNB2 on 8q13. We sequenced the BPs and identified a highly conserved Activator protein 1 (AP-1) motif on 12p11.2, together with a C-ets-1 motif translocated from 8q13. AP-1 and C-ets-1 bound in vitro and in vivo at the derivative chromosome 8 breakpoint [der(8) BP], but were differently enriched between the wild-type and BP allele. We differentiated fibroblasts from BDE patients into chondrogenic cells and found that PTHLH and its targets, ADAMTS-7 and ADAMTS-12 were downregulated along with impaired chondrogenic differentiation. We next used human and murine chondrocytes and observed that the AP-1 motif stimulated, whereas der(8) BP or C-ets-1 decreased, PTHLH promoter activity. These results are the first to identify a cis-directed PTHLH downregulation as primary cause of human chondrodysplasia.


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 8/genética , Regulação para Baixo , Dedos/anormalidades , Proteína Relacionada ao Hormônio Paratireóideo/genética , Sequências Reguladoras de Ácido Nucleico/genética , Dedos do Pé/anormalidades , Translocação Genética , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteína ADAMTS7 , Animais , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Humanos , Camundongos
8.
J Genet Genomics ; 47(10): 618-626, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33358777

RESUMO

Congenital hearing loss is a common disorder worldwide. Heterogeneous gene variation accounts for approximately 20-25% of such patients. We investigated a five-generation Chinese family with autosomal-dominant nonsyndromic sensorineural hearing loss (SNHL). No wave was detected in the pure-tone audiometry, and the auditory brainstem response was absent in all patients. Computed tomography of the patients, as well as of two sporadic SNHL cases, showed bilateral inner ear anomaly, cochlear maldevelopment, absence of the osseous spiral lamina, and an enlarged vestibular aqueduct. Such findings were absent in nonaffected persons. We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4KB gene (p.Gln121Arg) encoding phosphatidylinositol 4-kinase ß (PI4KB) from the patients in this family. In addition, 3 missense PI4KB (p.Val434Gly, p.Glu667Lys, and p.Met739Arg) mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases. No such mutations were present within 600 Chinese controls, the 1000 genome project, gnomAD, or similar databases. Depleting pi4kb mRNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment, mimicking the patient phenotypes. Moreover, overexpression of 4 human missense PI4KB mutant mRNAs in zebrafish embryos resulted in impaired hearing function, suggesting dominant-negative effects. Taken together, our results reveal that PI4KB mutations can cause SNHL and inner ear malformation. PI4KB should be included in neonatal deafness screening.


Assuntos
Predisposição Genética para Doença , Perda Auditiva Neurossensorial/genética , Doenças do Labirinto/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Animais , Cóclea/patologia , Orelha Interna/patologia , Feminino , Ligação Genética/genética , Perda Auditiva Neurossensorial/patologia , Humanos , Lactente , Recém-Nascido , Doenças do Labirinto/patologia , Masculino , Mutação de Sentido Incorreto/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento do Exoma , Peixe-Zebra/genética
9.
Ann Neurol ; 63(3): 323-8, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18306167

RESUMO

OBJECTIVE: Dysferlin (DYSF) gene mutations cause limb girdle muscular dystrophy type 2B and Miyoshi's myopathy. The consequences of DYSF mutations on protein structure are poorly understood. METHODS: The gene encoding dysferlin was sequenced in patients with suspected dysferlin-deficient muscular dystrophy. Muscle biopsy specimens were analyzed by histochemistry, immunohistochemistry, and electron microscopy. Antibodies against N-terminal dysferlin-peptides were raised. RESULTS: We found three families with muscular dystrophy caused by homozygous or compound heterozygous DYSF mutations featuring sarcolemmal and interstitial amyloid deposits. These mutations were all located in the N-terminal region of the protein. Dysferlin was a constituent of the amyloid deposits. INTERPRETATION: Limb girdle muscular dystrophy type 2B is the first muscular dystrophy associated with amyloidosis. Molecular treatment strategies will necessarily have to consider the presence of amyloidogenesis.


Assuntos
Amiloidose/genética , Amiloidose/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Adulto , Idoso , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Amiloidose/diagnóstico , Disferlina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Estrutura Terciária de Proteína/genética
10.
J Exp Med ; 214(7): 2089-2101, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28559244

RESUMO

CD177 presents antigens in allo- and autoimmune diseases on the neutrophil surface. Individuals can be either CD177-deficient or harbor distinct CD177neg and CD177pos neutrophil subsets. We studied mechanisms controlling subset-restricted CD177 expression in bimodal individuals. CD177pos, but not CD177neg neutrophils, produced CD177 protein and mRNA. Haplotype analysis indicated a unique monoallelic CD177 expression pattern, where the offspring stably transcribed either the maternal or paternal allele. Hematopoietic stem cells expressed both CD177 alleles and silenced one copy during neutrophil differentiation. ChIP and reporter assays in HeLa cells with monoallelic CD177 expression showed that methylation reduced reporter activity, whereas demethylation caused biallelic CD177 expression. HeLa cell transfection with c-Jun and c-Fos increased CD177 mRNA. Importantly, CD177pos human neutrophils, but not CD177neg neutrophils, showed a euchromatic CD177 promoter, unmethylated CpGs, and c-Jun and c-Fos binding. We describe epigenetic mechanisms explaining the two distinct CD177 neutrophil subsets and a novel monoallelic CD177 expression pattern that does not follow classical random monoallelic expression or imprinting.


Assuntos
Perfilação da Expressão Gênica/métodos , Inativação Gênica , Isoantígenos/genética , Neutrófilos/metabolismo , Receptores de Superfície Celular/genética , Alelos , Sequência de Bases , Diferenciação Celular/genética , Ilhas de CpG/genética , Metilação de DNA , Sangue Fetal/citologia , Sangue Fetal/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Células HeLa , Células-Tronco Hematopoéticas/metabolismo , Humanos , Immunoblotting , Isoantígenos/metabolismo , Regiões Promotoras Genéticas/genética , Receptores de Superfície Celular/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo
11.
Circ Res ; 90(9): 951-8, 2002 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-12016260

RESUMO

We studied a Syrian family with 3 children who had low-density lipoprotein cholesterol (LDL) concentrations of 13.3, 12.2, and 8.6 mmol/L, respectively. Three other siblings and the parents all had LDL values <4.52 mmol/L, suggesting an autosomal-recessive mode of inheritance. The extended pedigree had 66 additional persons with normal LDL values. A genome-wide scan in the core family with 427 markers showed support for linkage on both chromosomes 1 and 13. Markers on chromosome 1 revealed a 3.07 multipoint LOD score between 1p36.1-p35, an 18-cM interval. Surprisingly, we also found linkage to 13q22-q32, a 14-cM interval, with a 3.08 LOD score. We had identified this locus earlier as containing a gene strongly influencing LDL in another Arab family with autosomal-dominant familial hypercholesterolemia and in normal dizygotic twins. We found evidence for an interaction between these loci. We next genotyped our twin panel and confirmed linkage of the 1p36.1-p35 locus to LDL (P<0.002) in this normal population. Elucidation of ARH, the LDL receptor adaptor protein at chromosome 1p35, caused us to sequence that gene. We first identified the genomic structure of ARH gene and then sequenced the gene in our family. We found an intron 1 acceptor splice-site mutation. This mutation was not found in any other family members, in 31 nonrelated Syrian persons, or in 30 Germans. Our results underscore the importance of ARH on chromosome 1 and the chromosome 13q locus to LDL, not only in families with unusual illnesses, but also to the general population.


Assuntos
Colesterol/sangue , Cromossomos Humanos Par 13/genética , Hiperlipoproteinemia Tipo II/genética , Sequência de Bases , HDL-Colesterol/sangue , Cromossomos Humanos Par 1/genética , Saúde da Família , Feminino , Genes/genética , Genes Recessivos/genética , Ligação Genética , Genótipo , Haplótipos , Humanos , Hiperlipoproteinemia Tipo II/sangue , Escore Lod , Masculino , Repetições de Microssatélites , Mutação , Linhagem , Síria , Triglicerídeos/sangue
12.
J Mol Med (Berl) ; 83(2): 159-65, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15599693

RESUMO

We screened a white population for single nucleotide polymorphisms (SNPs) in five long QT syndrome genes, namely, KCNQ1 (LQT1), HERG (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). We found 35 SNPs, 10 of which have not been previously described. Ten SNPs were in KCNE1, six in HERG, eight in KCNQ1, four in KCNE2, and seven in SCN5A. Four SNPs were associated with QTc interval in our 141 subjects, one in KCNE1, one in KCNE2, and two in SCN5A. Two of these SNPs have not been described. We conclude that these five long QT syndrome genes contain common variants, some of which are associated with QTc interval in normal persons. We suggest that analysis of these SNPs in a much larger cohort would enable establishment of common haplotypes that are associated with QTc. These haplotypes could facilitate prediction of arrhythmia risk in the general population.


Assuntos
Síndrome do QT Longo/genética , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Análise Mutacional de DNA , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go , Testes Genéticos , Genótipo , Haplótipos , Humanos , Canais de Potássio KCNQ , Canal de Potássio KCNQ1 , Canal de Sódio Disparado por Voltagem NAV1.5 , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Fatores de Risco , Canais de Sódio/genética , Estudos em Gêmeos como Assunto
13.
Dtsch Med Wochenschr ; 140(25): 1920-3, 2015 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-26676478

RESUMO

Mendelian conditions direct attention at basic mechanisms. In the 1990's DNA sequencing allowed elucidating such conditions. We embarked on an unexpected adventure to study a monogenic autosomal-dominant form of hypertension causing also a specific form of short fingers. The gene locus caused a 50 mmHg increase in blood pressure at age of 50. Our clinically based group stumbled to the finish line after 20 years of study. We remained together and proudly persevered. Our findings could be relevant for essential hypertension.


Assuntos
Hipertensão/genética , Hipertensão/fisiopatologia , Genótipo , Técnicas de Genotipagem , Humanos , Hipertensão/diagnóstico , Hipertensão/terapia , Fenótipo , Análise de Sequência de DNA
14.
Hypertension ; 66(4): 800-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26283042

RESUMO

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.


Assuntos
Braquidactilia/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , DNA/genética , Hipertensão/congênito , Mutação , Adolescente , Adulto , Pressão Sanguínea/fisiologia , Braquidactilia/diagnóstico , Braquidactilia/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Análise Mutacional de DNA , Ecocardiografia Doppler de Pulso , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/enzimologia , Hipertensão/genética , Immunoblotting , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Nat Genet ; 47(6): 647-53, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25961942

RESUMO

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.


Assuntos
Braquidactilia/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Hipertensão/congênito , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Estudos de Casos e Controles , Diferenciação Celular , Criança , Feminino , Estudos de Associação Genética , Células HeLa , Humanos , Hipertensão/genética , Cinética , Masculino , Células-Tronco Mesenquimais/fisiologia , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Miócitos de Músculo Liso/fisiologia , Linhagem
16.
J Hypertens ; 20(5): 927-33, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12011654

RESUMO

BACKGROUND: The baroreflex, which is important for the minute-to-minute regulation of blood pressure and heart rate, is influenced by genetic variance. Ion channels are important to baroreflex afferent and efferent function. Mice missing the beta1 subunit of the Ca2+-sensitive potassium channel (BK) are hypertensive and have a reset baroreflex. We tested the hypothesis that variants in the gene (KCNMB1) coding for the BK beta1 subunit are associated with baroreflex function. METHODS: We studied six single-nucleotide polymorphisms (SNPs) in KCNMB1. RESULTS: Four SNPs in intron 3, exon 4a, exon 4b and exon 4c gave significant results. For instance, exon 4b SNP AA individuals had higher heart rate variability, compared to CA, or CC persons, in particular in the high-frequency range. The low-frequency range showed no association. Consistent with the heart rate variability data, homozygous AA persons had greater baroreflex slopes than CA or CC persons, also in the high-frequency range. These associations could not be shown in the low-frequency range for heart rate variability and baroreflex slopes. CONCLUSIONS: These data support the notion that variants in channel genes may be responsible for the great range in heart rate variability and baroreflex function observed in humans. Such variation may also play a role in the development of hypertension.


Assuntos
Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Canais de Potássio Cálcio-Ativados/genética , Adulto , Barorreflexo/genética , Pressão Sanguínea/genética , Feminino , Homozigoto , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/fisiologia , Gêmeos Dizigóticos , Gêmeos Monozigóticos
17.
J Mol Med (Berl) ; 92(4): 337-46, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24531795

RESUMO

Long non-coding RNAs (lncRNAs) interact with the nuclear architecture and are involved in fundamental biological mechanisms, such as imprinting, histone-code regulation, gene activation, gene repression, lineage determination, and cell proliferation, all by regulating gene expression. Understanding the lncRNA regulation of transcriptional or post-transcriptional gene regulation expands our knowledge of disease. Several associations between altered lncRNA function and gene expression have been linked to clinical disease phenotypes. Early advances have been made in developing lncRNAs as biomarkers. Several mouse models reveal that human lncRNAs have very diverse functions. Their involvement in gene and genome regulation as well as disease underscores the importance of lncRNA-mediated regulatory networks. Because of their tissue-specific expression potential, their function as activators or repressors, and their selective targeting of genes, lncRNAs are of potential therapeutic interest. We review the regulatory mechanisms of lncRNAs, their major functional principles, and discuss their role in Mendelian disorders, cancer, cardiovascular disease, and neurological disorders.


Assuntos
Epigênese Genética , RNA Longo não Codificante/fisiologia , Animais , Sequência de Bases , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo
18.
J Clin Invest ; 122(11): 3990-4002, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23093776

RESUMO

Translocations are chromosomal rearrangements that are frequently associated with a variety of disease states and developmental disorders. We identified 2 families with brachydactyly type E (BDE) resulting from different translocations affecting chromosome 12p. Both translocations caused downregulation of the parathyroid hormone-like hormone (PTHLH) gene by disrupting the cis-regulatory landscape. Using chromosome conformation capturing, we identified a regulator on chromosome 12q that interacts in cis with PTHLH over a 24.4-megabase distance and in trans with the sex-determining region Y-box 9 (SOX9) gene on chromosome 17q. The element also harbored a long noncoding RNA (lncRNA). Silencing of the lncRNA, PTHLH, or SOX9 revealed a feedback mechanism involving an expression-dependent network in humans. In the BDE patients, the human lncRNA was upregulated by the disrupted chromosomal association. Moreover, the lncRNA occupancy at the PTHLH locus was reduced. Our results document what we believe to be a novel in cis- and in trans-acting DNA and lncRNA regulatory feedback element that is reciprocally regulated by coding genes. Furthermore, our findings provide a systematic and combinatorial view of how enhancers encoding lncRNAs may affect gene expression in normal development.


Assuntos
Braquidactilia , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 17 , Regulação da Expressão Gênica , Loci Gênicos , RNA Longo não Codificante , Translocação Genética , Animais , Braquidactilia/diagnóstico por imagem , Braquidactilia/genética , Braquidactilia/metabolismo , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 12/metabolismo , Feminino , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Proteína Relacionada ao Hormônio Paratireóideo/genética , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , Radiografia , Fatores de Transcrição SOX9/biossíntese , Fatores de Transcrição SOX9/genética
20.
Hypertension ; 56(5): 988-94, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20837885

RESUMO

Affected individuals with autosomal-dominant hypertension with brachydactyly syndrome develop severe progressive hypertension and, if left untreated, develop stroke by age <50 years. In 1996 we described hypertension and brachydactyly and presented data on adults. We recently revisited this family and performed further studies, focusing particularly on the children in this family. We performed a genome-wide single-nucleotide polymorphism genotyping linkage analysis and confirmed our earlier linkage results. We accrued interesting ancillary data that we attribute to the rearrangements that we described earlier. We performed additional analysis focused on providing clinical criteria for the diagnosis in children and particularly to monitor the onset and to display the age-dependent development of hypertension and brachydactyly. We investigated 30 children; 12 were affected, whereas 18 were not. Brachydactyly with short stature presented as a maturing phenotype, becoming obvious during the prepubertal growth spurt. Stage 2 hypertension was already present in toddlers and increased with age. Thus, blood pressure measurement, rather than brachydactyly, was the most reliable phenotype for the very early diagnosis in children. Importantly, hypertension with brachydactyly occurs worldwide. Once the diagnosis is made, we recommend treatment of all individuals with stage 2 hypertension according to the current European and US guidelines on hypertension in children and adolescents.


Assuntos
Estatura/genética , Hipertensão/genética , Deformidades Congênitas dos Membros/genética , Puberdade/genética , Adolescente , Criança , Pré-Escolar , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipertensão/complicações , Lactente , Deformidades Congênitas dos Membros/complicações , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único
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