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1.
Org Biomol Chem ; 20(17): 3598-3604, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35420107

RESUMO

Herein we report the development of a sequential synthesis route towards annulated imidazo[4,5-c]isoquinolines comprising a GBB-3CR, followed by an intramolecular imidoylative cyclisation. X-Ray crystallography revealed a flat 3D structure of the obtained polyheterocycles. Thus, we evaluated their interactions with double-stranded DNA by establishing a pUC-19 plasmid-based gel electrophoresis mobility shift assay, revealing a stabilising effect on ds-DNA against strand-break inducing conditions.


Assuntos
DNA , Isoquinolinas , Ciclização , Eletroforese em Gel de Poliacrilamida , Ensaio de Desvio de Mobilidade Eletroforética , Isoquinolinas/química , Plasmídeos
2.
Hautarzt ; 72(4): 288-294, 2021 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-33661338

RESUMO

Hereditary tumor syndromes are characterized by a familial occurrence of tumors/cancer. A hereditary tumor syndrome should be suspected if a familial occurrence of cancer is seen and/or persons at younger age are affected. Some of the currently known tumor syndromes are associated with specific skin symptoms that can aid the physician in establishing the correct diagnosis. Examples are fibrofolliculoma in Birt-Hogg-Dubé syndrome, epidermal cysts, sebaceous cysts, neurofibroma in Gardner syndrome and sebaceous neoplasms or keratoacanthoma in Muir-Torre syndrome. If a genetic tumor syndrome is suspected, genetic testing and counselling should be performed in the index patient and is also recommended for family members. Affected patients should be offered regular clinical surveillance by the appropriate medical disciplines. Since curative therapy does not exist so far, preventive screening is of great importance.


Assuntos
Síndrome de Birt-Hogg-Dubé , Síndromes Neoplásicas Hereditárias , Neoplasias das Glândulas Sebáceas , Dermatopatias , Neoplasias Cutâneas , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia
3.
BMC Med Genet ; 19(1): 45, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29548312

RESUMO

BACKGROUND: Birt-Hogg-Dubé syndrome is a genetic syndrome caused by mutations in the FLCN gene. The main symptoms are lung bullae and pneumothorax, benign and malignant kidney tumors, and facial fibrofolliculoma. The risk of pneumothorax is considerable between ages 20-40 years, but decreases markedly after this age range and first-time pneumothorax after age 50 years is rare. Fibrofolliculomas usually occur between ages 35 and 45 years, while the risk for kidney cancer increases steadily with age, starting in young adulthood. However, we demonstrate here that within the same family patients might develop symptoms significantly before or after the usual age range, obscuring the typical clinical pattern and delaying diagnosis. CASE PRESENTATION: The 43 year old index patient had a history of lung bullae and recurrent pneumothoraces starting 14 years earlier. His father (age 83 years) and one of the paternal uncles experienced their first pneumothorax unusually late after the age of 60 years. The uncle subsequently had four more pneumothoraces, and was diagnosed with kidney in his early 70s. Considerable differences in age of onset were also observed with regard to facial fibrofolliculomas that both paternal uncles developed very early around age 20 years, but which the father only started to show in his eighth decade. Birt-Hogg-Dubé syndrome was finally diagnosed when the index patient started to develop fibrofolliculomas within the typical age range. CONCLUSIONS: The family described here illustrates that Birt-Hogg-Dubé syndrome can be difficult to recognize, if presenting with considerable intrafamilial clinical variability. With a life-time kidney cancer risk of about 14-35% the consequences of delayed diagnosis might be grave for the affected family members. The possibility of Birt-Hogg-Dubé syndrome should therefore be taken into consideration in apparently sporadic patients presenting with lung bullae and pneumothorax.


Assuntos
Síndrome de Birt-Hogg-Dubé/diagnóstico , Síndrome de Birt-Hogg-Dubé/genética , Diagnóstico Tardio , Adulto , Sequência de Bases , Predisposição Genética para Doença , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Pneumopatias/diagnóstico , Pneumopatias/genética , Masculino , Mutação , Linhagem , Pneumotórax/diagnóstico , Pneumotórax/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Risco , Proteínas Supressoras de Tumor/genética
5.
PLoS One ; 11(4): e0152984, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27054571

RESUMO

Variation in genes coding for nicotinic acetylcholine receptor (nAChR) subunits affect cognitive processes and may contribute to the genetic architecture of neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in the CHRNA4 gene that codes for the alpha4 subunit of alpha4/beta2-containing receptors have previously been implicated in aspects of (mostly visual) attention and smoking-related behavioral measures. Here we investigated the effects of six synonymous but functional CHRNA4 exon 5 SNPs on the N100 event-related potential (ERP), an electrophysiological endophenotype elicited by a standard auditory oddball. A total of N = 1,705 subjects randomly selected from the general population were studied with electroencephalography (EEG) as part of the German Multicenter Study on nicotine addiction. Two of the six variants, rs1044396 and neighboring rs1044397, were significantly associated with N100 amplitude. This effect was pronounced in females where we also observed an effect on reaction time. Sequencing of the complete exon 5 region in the population sample excluded the existence of additional/functional variants that may be responsible for the observed effects. This is the first large-scale population-based study investigation the effects of CHRNA4 SNPs on brain activity measures related to stimulus processing and attention. Our results provide further evidence that common synonymous CHRNA4 exon 5 SNPs affect cognitive processes and suggest that they also play a role in the auditory system. As N100 amplitude reduction is considered a schizophrenia-related endophenotype the SNPs studied here may also be associated with schizophrenia outcome measures.


Assuntos
Polimorfismo de Nucleotídeo Único/genética , Receptores Nicotínicos/genética , Fumar/efeitos adversos , Tabagismo/genética , Adulto , Fenômenos Eletrofisiológicos , Endofenótipos , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Neuroimagem , Tabagismo/epidemiologia , Tabagismo/patologia
6.
Mol Cell Endocrinol ; 399: 103-9, 2015 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-25258300

RESUMO

The cannabinoid receptor subtype 1 gene CNR1 is not only associated with phenotypes such as cognitive performance, addiction and anxiety, but is also known to be crucially involved in responses to acute and chronic psychological and cellular stress conditions. Functional analysis of the 5' untranslated regions of the five known mRNA variants of the human CNR1 gene revealed that two of these variants contain upstream open reading frames that are able to modulate gene expression both under baseline condition and conditions of cellular stress including hypoxia, glucose restriction and hyperthermia. The upstream open reading frames might provide a mechanism that enables the cannabinoid 1 receptor to escape the general repression of protein synthesis that is typical for conditions of cellular stress.


Assuntos
Regiões 5' não Traduzidas/fisiologia , Regulação da Expressão Gênica/fisiologia , Fases de Leitura Aberta/fisiologia , Receptor CB1 de Canabinoide/biossíntese , Estresse Fisiológico , Células HEK293 , Humanos
9.
Biochem Pharmacol ; 76(10): 1175-83, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18691557

RESUMO

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated channels that mediate, in the peripheral nervous system, fast neurotransmission at the neuromuscular junction and in ganglia. Widely expressed in the central nervous system neuronal nAChRs are thought to contribute both to neurotransmission and modulation of neuronal activity. To date, eleven genes encoding for these receptors have been identified in the mammalian genome and their structure is well conserved throughout evolution. Progresses made in the field of genetics and the identification of a large number of small genetic variants such as single nucleotide polymorphisms raise new questions about the physiologic and pharmacologic consequences of such variations. The finding of associations between polymorphisms in the genes encoding for the neuronal nAChRs and neurological disorders such as schizophrenia and Alzheimer disease illustrate the importance of getting a better understanding of these receptors from the gene to function. In this work we present an overview over the progress that has been made in understanding the role of nAChR genes in monogenic disorders such as familial epilepsy, and review the latest knowledge about genetic variants of the nAChR genes and their relationship with common disorders and behavioural traits of complex etiology.


Assuntos
Doenças do Sistema Nervoso/genética , Receptores Nicotínicos/genética , Animais , Técnicas Genéticas/tendências , Humanos , Mutação/genética , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/metabolismo , Neurônios/fisiologia , Receptores Nicotínicos/metabolismo
10.
Eur J Pediatr ; 167(7): 827-8, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17676340

RESUMO

Consanguinity is not the only factor influencing the occurrence of autosomal recessive disorders such as familial Mediterranean fever (FMF). The extended, multiple consanguineous Turkish pedigree presented here demonstrates that the population frequency of certain mutations (so-called "ancient" mutations) can be at least equally important. In high-risk populations different combinations of mutations can occur within the same family, increasing not only the intrafamilial clinical variability, but also causing considerable recurrence risks even in marriages with unrelated spouses.


Assuntos
Febre Familiar do Mediterrâneo/genética , Linhagem , Adulto , Consanguinidade , Febre Familiar do Mediterrâneo/epidemiologia , Genética Populacional , Humanos , Mutação , Turquia/epidemiologia
11.
Epilepsy Res ; 73(3): 245-9, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17129708

RESUMO

BACKGROUND: Benign familial neonatal convulsions (BFNC) is a rare autosomal dominant seizure disorder usually described to be characterized by a benign course, spontaneous remission and normal psychomotor development. The latter statement had come under consideration when a few case reports of families with less than favorable outcomes were published. METHODS: Since 1998 a total of 112 families suspected to have BFNC have been referred to our lab for genetic testing. Within this sample we identified private KCNQ2 mutations in 17 BFNC families. For 10 of those 17 families follow up information about the psychomotor development and the outcome were available. RESULTS: In 4 (40%) of the 10 families at least 1 affected individual showed delayed psychomotor development or mental retardation. Three of the four mutations were familial, while the fourth mutation was de novo. Mutations associated with an unfavorable outcome tended to be located within the functionally critical S5/S6 regions of the KCNQ2 gene. CONCLUSIONS: Our data raise the question if BFNC can indeed be described as a benign disorder, and which are the genetic and/or environmental factors that influence the outcome.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia Neonatal Benigna/genética , Canal de Potássio KCNQ2/genética , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia Neonatal Benigna/complicações , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Mutação , Linhagem , Prognóstico
12.
Neurogenetics ; 6(2): 59-66, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15827762

RESUMO

The leucine-rich, glioma inactivated gene 1 (LGI1) gene on human chromosome 10q24 was first identified as a candidate tumor suppressor gene for glioma. Surprisingly, mutations in LGI1 were also shown to cause an idiopathic epilepsy syndrome, autosomal dominant lateral temporal lobe epilepsy (ADLTE). LGI1 is one of the only two currently known non-ion channel genes whose mutations cause idiopathic epilepsy in humans. In this review we summarize the current data on structure and function of the LGI1 protein and discuss clinical aspects of ADLTE and their correlation with LGI1. We also propose that the evidence supporting the tumor suppressor role of LGI1 in malignant gliomas is weak and that further work is necessary to establish LGI1 role in glial cells.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Epilepsia do Lobo Temporal/fisiopatologia , Glioma/fisiopatologia , Proteínas/genética , Neoplasias Encefálicas/genética , Epilepsia do Lobo Temporal/genética , Glioma/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular
13.
Vet Rec ; 153(25): 779-81, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14735994

RESUMO

A congenital myasthenic syndrome in Brahman cattle is caused by a homozygous 20 base pair deletion (470del20) in the gene coding for the epsilon subunit of the acetylcholine receptor at the neuromuscular junction. It causes a progressive muscle weakness starting either at birth or within the first month. A PCR-based DNA test, using blood or semen stored on FTA paper, was developed and validated; the test makes it possible to differentiate rapidly and accurately between homozygous wild-type, heterozygous and homozygous affected animals. Preliminary testing of Brahman cattle in South Africa has revealed several carrier animals, some of them influential animals in the breeding population.


Assuntos
Doenças dos Bovinos/diagnóstico , Doenças dos Bovinos/genética , DNA/análise , Predisposição Genética para Doença , Síndromes Miastênicas Congênitas/veterinária , Receptores Colinérgicos/genética , Animais , Animais Recém-Nascidos , Bovinos , Doenças dos Bovinos/epidemiologia , Masculino , Mutação , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/genética , Linhagem , Reação em Cadeia da Polimerase/veterinária , Valor Preditivo dos Testes , Sêmen , África do Sul/epidemiologia
16.
Neuroreport ; 12(17): 3733-9, 2001 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-11726784

RESUMO

Benign familial neonatal convulsions (BFNC) have been previously found to be associated with mutations within the coding region of KCNQ2. We have now cloned and analyzed the promoter region of the human KCNQ2 gene. 5'-RACE identified a transcription start site (TSS) located 200 bp upstream of the ATG start codon. The TSS is located close to a repetitive region containing seven copies of a degenerate 42-mer repeat. Several different luciferase (LUC) reporter plas- mids containing fragments from the KCNQ2 5'-flanking region were constructed and expressed in NT2N and SH-SY5Y cell lines. A core promoter region was found to be located between bp 20 and bp 74 upstream of the TSS. Neither the promoter region nor the repetitive region showed any mutations in 13 index patients from unrelated BFNC families.


Assuntos
Potenciais de Ação/genética , Encéfalo/metabolismo , Clonagem Molecular , Epilepsia Neonatal Benigna/genética , Canais de Potássio/genética , Regiões Promotoras Genéticas/genética , Região 5'-Flanqueadora/genética , Animais , Sequência de Bases/genética , Encéfalo/fisiopatologia , Análise Mutacional de DNA , Epilepsia Neonatal Benigna/fisiopatologia , Genes Reporter/genética , Testes Genéticos , Vetores Genéticos/genética , Humanos , Canal de Potássio KCNQ2 , Luciferases/genética , Camundongos , Dados de Sequência Molecular , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Homologia de Sequência do Ácido Nucleico , Transcrição Gênica/genética , Transfecção , Células Tumorais Cultivadas
17.
Am J Med Genet ; 106(2): 139-45, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11579434

RESUMO

Partial or generalized idiopathic epilepsies, which account for up to 40% of all epilepsies, are characterized by a mostly benign course and no apparent etiology other than a genetic predisposition. So far, the genetic defects underlying three different idiopathic epilepsy syndromes have been identified: mutations in the CHRNA4- or CHRNB subunits of the neuronal nicotinic acetylcholine receptor are found in familial nocturnal frontal lobe epilepsy, while defects in the voltage-gated potassium channels KCNQ2 and KCNQ3 have recently been identified in benign familial neonatal convulsions. The syndrome of "generalized epilepsy with febrile seizures plus" can be caused by mutations affecting the voltage-gated sodium channel subunits SCN1B and SCN1A or the gamma 2-subunit of the GABA(A) receptor. The results of recent molecular studies contributed largely to our understanding of the etiology and pathophysiology of idiopathic epilepsies.


Assuntos
Epilepsia/genética , Mutação/genética , Epilepsias Parciais/genética , Epilepsias Parciais/metabolismo , Epilepsia/metabolismo , Epilepsia Neonatal Benigna/genética , Epilepsia Neonatal Benigna/metabolismo , Epilepsia Generalizada/genética , Epilepsia Generalizada/metabolismo , Humanos , Mutação Puntual , Canais de Potássio/genética , Canais de Potássio/metabolismo , Receptores Colinérgicos/genética , Receptores Colinérgicos/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Convulsões Febris/genética , Convulsões Febris/metabolismo , Canais de Sódio/genética , Canais de Sódio/metabolismo
19.
Proc Natl Acad Sci U S A ; 98(21): 12272-7, 2001 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-11572947

RESUMO

KCNQ2 and KCNQ3 are two homologous K(+) channel subunits that can combine to form heterotetrameric channels with properties of neuronal M channels. Loss-of-function mutations in either subunit can lead to benign familial neonatal convulsions (BFNC), a generalized, idiopathic epilepsy of the newborn. We now describe a syndrome in which BFNC is followed later in life by myokymia, involuntary contractions of skeletal muscles. All affected members of the myokymia/BFNC family carried a mutation (R207W) that neutralized a charged amino acid in the S4 voltage-sensor segment of KCNQ2. This substitution led to a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization. Myokymia is thought to result from hyperexcitability of the lower motoneuron, and indeed both KCNQ2 and KCNQ3 mRNAs were detected in the anterior horn of the spinal cord where the cells of the lower motoneurons arise. We propose that a difference in firing patterns between motoneurons and central neurons, combined with the drastically slowed voltage activation of the R207W mutant, explains why this particular KCNQ2 mutant causes myokymia in addition to BFNC.


Assuntos
Epilepsia Neonatal Benigna/genética , Mutação , Mioquimia/genética , Canais de Potássio/genética , Adulto , Animais , Animais Recém-Nascidos , Condutividade Elétrica , Eletrofisiologia , Epilepsia Neonatal Benigna/patologia , Epilepsia Neonatal Benigna/fisiopatologia , Feminino , Humanos , Hibridização In Situ , Canal de Potássio KCNQ2 , Canal de Potássio KCNQ3 , Masculino , Mioquimia/patologia , Mioquimia/fisiopatologia , Linhagem , Canais de Potássio/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Medula Espinal/metabolismo , Medula Espinal/patologia , Síndrome , Xenopus laevis
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