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1.
Clin Genet ; 105(6): 655-660, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38384171

RESUMO

Precise regulation of gene expression is important for correct neurodevelopment. 9q34.3 deletions affecting the EHMT1 gene result in a syndromic neurodevelopmental disorder named Kleefstra syndrome. In contrast, duplications of the 9q34.3 locus encompassing EHMT1 have been suggested to cause developmental disorders, but only limited information has been available. We have identified 15 individuals from 10 unrelated families, with 9q34.3 duplications <1.5 Mb in size, encompassing EHMT1 entirely. Clinical features included mild developmental delay, mild intellectual disability or learning problems, autism spectrum disorder, and behavior problems. The individuals did not consistently display dysmorphic features, congenital anomalies, or growth abnormalities. DNA methylation analysis revealed a weak DNAm profile for the cases with 9q34.3 duplication encompassing EHMT1, which could segregate the majority of the affected cases from controls. This study shows that individuals with 9q34.3 duplications including EHMT1 gene present with mild non-syndromic neurodevelopmental disorders and DNA methylation changes different from Kleefstra syndrome.


Assuntos
Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 9 , Metilação de DNA , Cardiopatias Congênitas , Histona-Lisina N-Metiltransferase , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Metilação de DNA/genética , Cromossomos Humanos Par 9/genética , Masculino , Feminino , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Duplicação Cromossômica/genética , Criança , Pré-Escolar , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Adolescente , Fenótipo
2.
Scand J Immunol ; 99(1): e13323, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37801334

RESUMO

BACKGROUND: C-reactive protein (CRP) is lower in patients who carry the apolipoprotein E epsilon 4 allele variant (APOEε4) of the APOE gene. This could however be explained by other factors observed in APOEε4 carriers, such as lower body mass index (BMI), possibly less diabetes and more use of statins, all associated with CRP concentrations. OBJECTIVES: To assess the association between CRP and APOEε4 stratified by BMI, statin use and diabetes. METHODS: We included 2700 community-dwelling older adults from the Hordaland health study with genotyping of the APOE gene by a one-step polymerase chain reaction and CRP measured using immuno-MALDI-TOF MS. Differences in CRP concentrations by APOE (ε4 vs no ε4) were assessed using the Mann-Whitney U tests, also stratified by statin use, diabetes and BMI categories. Finally, we performed linear regression with log (CRP) as the outcome and APOEε4 together with statin use, diabetes, BMI and their respective interactions. RESULTS: CRP was higher in APOEε4 carriers irrespective of BMI, diabetes and statin use. In APOEε4 non-carriers, CRP was elevated with diabetes and obesity as expected. However, this was attenuated or even reversed in APOEε4 carriers. Such differences were not observed for statin use. CONCLUSIONS: Statin use, obesity or diabetes did not confound the known association between the APOEε4 allele and lower CRP. Our data suggest that CRP is less responsive to inflammatory cues involved in diabetes and obesity in APOEε4 carriers. Epidemiological studies should take note of these relationships, as CRP, APOEε4, diabetes and obesity are both linked to neurodegenerative and cardiovascular disease.


Assuntos
Diabetes Mellitus , Inibidores de Hidroximetilglutaril-CoA Redutases , Idoso , Humanos , Alelos , Apolipoproteínas E/genética , Proteína C-Reativa/metabolismo , Diabetes Mellitus/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Obesidade/genética
3.
Acta Ophthalmol ; 99(5): e733-e746, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33258285

RESUMO

PURPOSE: Pathogenic variations in the ABCA4 gene are a leading cause of vision loss in patients with inherited retinal diseases. ABCA4-retinal dystrophies are clinically heterogeneous, presenting with mild to severe degeneration of the retina. The purpose of this study was to clinically and genetically characterize patients with ABCA4-retinal dystrophies in Norway and describe phenotype-genotype associations. METHODS: ABCA4 variants were detected in 111 patients with inherited retinal disease undergoing diagnostic genetic testing over a period of 12 years. In patients where only a single ABCA4 variant was found, whole-gene ABCA4 sequencing was performed and intronic variants were investigated by mRNA analyses in fibroblasts. Medical journals were used to obtain a clinical description and ultrawidefield autofluorescence images were used to analyse retinal degeneration patterns. RESULTS: The genetic diagnostic yield was 89%. The intronic splice variant c.5461-10T>C was the most prevalent disease-causing variant (27%). Whole-gene ABCA4 sequencing detected two novel intronic variants (c.6729+81G>T and c.6817-679C>A) that we showed affected mRNA splicing. Peripheral retinal degeneration was identified in 33% of patients and was associated with genotypes that included severe loss of function variants. By contrast, peripheral degeneration was not found in patients with a disease duration over 20 years and genotypes including p.(Asn1868lle), c.4253+43G>A or p.(Gly1961Glu) in trans with a loss of function variant. CONCLUSION: This study demonstrates the clinical and genetic heterogeneity of ABCA4-retinal dystrophies in Norway. Further, the study presents novel variants and increases our knowledge on phenotype-genotype associations and the presence of peripheral retinal degeneration in ABCA4-retinal dystrophy patients.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , DNA/genética , Estudos de Associação Genética/métodos , Mutação , Distrofias Retinianas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Heterogeneidade Genética , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Linhagem , Fenótipo , Distrofias Retinianas/epidemiologia , Distrofias Retinianas/metabolismo , Segmento Externo da Célula Bastonete , Adulto Jovem
4.
Scand J Pain ; 10: 43-51, 2016 01.
Artigo em Inglês | MEDLINE | ID: mdl-28361770

RESUMO

BACKGROUND AND AIMS: Peripheral neuropathic pain is described as a pain state caused by an injury or dysfunction of the nervous system, and could have clinical manifestations such as hyperalgesia, allodynia and spontaneous pain. The development of neuropathic pain may depend on long-term forms of neuronal plasticity in the spinal cord (SC). Expression of the immediate early gene proteins (IEGPs) Arc, Zif268, and c-Fos are implicated in establishment of long-term potentiation (LTP) induced by conditioning stimulation (CS) of primary afferent fibres. However, the impact of the neuropathic state (Bennett's model) on CS-induced expression of IEGPs has not been studied. The aim of this study was to compare the levels of Arc, c-Fos and Zif268 immunoreactivity prior to and after conditioning stimulation in animals with developed neuropathic pain, with sham operated, non-ligated controls. METHODS: Twenty-four animals were divided equally into the neuropathic and non-neuropathic groups. Neuropathic pain was induced in all animals by conducting a loose ligation of the sciatic nerve with Chromic Catgut 4.0 sutures 7 days prior to conditioning stimulation or sham operation. The loose ligation was performed by placing sutures around the sciatic nerve compressing the nerve slightly just enough to reduce but not completely diminish the perineural circulation. A state of neuropathy was confirmed by a significant decrease in mechanical withdrawal threshold measured by von Frey's fibres. Immunohistochemical analysis was performed on transverse sections obtained from the L3-L5 segments of the SC at 2 and 6h post-CS and IEGP positive cells were counted in lamina I and II of the dorsal horn. During statistical analyses, the groups were compared by means of analysis of variance (univariate general linear model). If significant differences were found, each set of animals was compared with the sham group with post hoc Tukey's multiple comparison test. RESULTS: Strikingly, all IEGPs exhibited a significant increase in immunoreactivity at both time points compared to time-matched, sham operated controls. Maximal IEGP expression was found 2h after CS in neuropathic rats, and there was a smaller but still significant increase 6h after CS. The unstimulated side of the dorsal horn in stimulated animals did not show any significant change of the number of IEGP positive cells and was approximately at the same level as sham operated animals. The number of IEGP positive cells in sham operated controls (non-neuropathic and non-stimulated animals) showed same immunoreactivity in 2 and 6h post sham operation. CONCLUSIONS AND IMPLICATIONS: The neurophysiological process of neuropathic pain development is complex and needs to be studied further in order to clarify its nature and components. This present study is meant to reveal a step towards further understanding the role of Arc, c-Fos and Zif268 in neuropathic pain. Moreover, this study might contribute to the knowledge base for further research on better therapeutic possibilities for neuropathic pain.


Assuntos
Genes Precoces , Proteínas Imediatamente Precoces/genética , Neuralgia/genética , Animais , Proteínas do Citoesqueleto/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal
5.
Acta Neurobiol Exp (Wars) ; 75(3): 305-13, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26581386

RESUMO

Synaptic plasticity is a property of neurons that can be induced by conditioning electrical stimulation (CS) of afferent fibers in the spinal cord. This is a widely studied property of spinal cord and hippocampal neurons. CS has been shown to trigger enhanced expression of immediate early gene proteins (IEGPs), with peak increases observed 2 hour post stimulation. Chronic morphine treatment has been shown to promoteinduce opioid-induced hyperalgesia, and also to increase CS-induced central sensitization in the dorsal horn. As IEGP expression may contribute to development of chronic pain states, we aimed to determine whether chronic morphine treatment affects the expression of IEGPs following sciatic nerve CS. Changes in expression of the IEGPs Arc, c-Fos or Zif268 were determined in cells of the lumbar dorsal horn of the spinal cord. Chronic Morphine pretreatment over 7 days led to a significant increase in the number of IEGP positive cells observed at both 2 h and 6 h after CS. The same pattern of immunoreactivity was obtained for all IEGPs, with peak increases occurring at 2 h post CS. In contrast, morphine treatment alone in sham operated animals had no effect on IEGP expression. We conclude that chronic morphine treatment enhances stimulus-induced expression of IEGPs in the lumbar dorsal horn. These data support the notion that morphine alters gene expression responses linked to nociceptive stimulation and plasticity.


Assuntos
Analgésicos Opioides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Imediatamente Precoces/metabolismo , Morfina/farmacologia , Nervo Isquiático/fisiologia , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Complexo Relacionado com a AIDS/genética , Complexo Relacionado com a AIDS/metabolismo , Vias Aferentes/fisiologia , Análise de Variância , Animais , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Estimulação Elétrica , Feminino , Proteínas Imediatamente Precoces/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/metabolismo , Fatores de Tempo
6.
PLoS One ; 10(4): e0123604, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25860146

RESUMO

Long-term potentiation induced by conditioning electrical stimulation of afferent fibers is a widely studied form of synaptic plasticity in the brain and the spinal cord. In the spinal cord dorsal horn, long-term potentiation is induced by a series of high-frequency trains applied to primary afferent fibers. Conditioning stimulation (CS) of sciatic nerve primary afferent fibers also induces expression of immediate early gene proteins in the lumbar spinal cord. However, the time course of immediate early gene expression and the rostral-caudal distribution of expression in the spinal cord have not been systematically studied. Here, we examined the effects of sciatic nerve conditioning stimulation (10 stimulus trains, 0.5 ms stimuli, 7.2 mA, 100 Hz, train duration 2 s, 8 s intervals between trains) on cellular expression of immediate early genes, Arc, c-Fos and Zif268, in anesthetized rats. Immunohistochemical analysis was performed on sagittal sections obtained from Th13- L5 segments of the spinal cord at 1, 2, 3, 6 and 12 h post-CS. Strikingly, all immediate early genes exhibited a monophasic increase in expression with peak increases detected in dorsal horn neurons at 2 hours post-CS. Regional analysis showed peak increases at the location between the L3 and L4 spinal segments. Both Arc, c-Fos and Zif268 remained significantly elevated at 2 hours, followed by a sharp decrease in immediate early gene expression between 2 and 3 hours post-CS. Colocalization analysis performed at 2 hours post-CS showed that all c-Fos and Zif268 neurons were positive for Arc, while 30% and 43% of Arc positive neurons were positive for c-Fos and Zif268, respectively. The present study identifies the spinal cord level and time course of immediate early gene (IEGP) expression of relevance for analysis of IEGPs function in neuronal plasticity and nociception.


Assuntos
Expressão Gênica , Genes Precoces , Nervo Isquiático/metabolismo , Medula Espinal/metabolismo , Animais , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Estimulação Elétrica , Feminino , Espaço Intracelular/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Transporte Proteico , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Fatores de Tempo
7.
Clin Interv Aging ; 8: 1539-46, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24255598

RESUMO

BACKGROUND: Chronic heart failure is a very common condition in the elderly, characterized not only by high mortality rates, but also by a strong impact on health-related quality of life (HRQOL). Previous studies of HRQOL in elderly heart failure subjects have included mostly outpatients, and little is known about determinants of HRQOL in hospitalized elderly population, especially in Serbia. In this study, we tried to identify factors that influence HRQOL in elderly patients hospitalized with chronic heart failure in Serbia. METHODS: The study population consisted of 136 patients aged 65 years or older hospitalized for chronic heart failure. HRQOL was assessed using the Minnesota Living with Heart Failure questionnaire. Predictors of HRQOL were identified by multiple linear regression analysis. RESULTS: Univariate analysis showed that patients with lower income, a longer history of chronic heart failure, and longer length of hospital stay, as well as those receiving aldosterone antagonists and digoxin, taking multiple medications, in a higher NYHA class, and showing signs of depression and cognitive impairment had significantly worse HRQOL. Presence of depressive symptoms (P<0.001), higher NYHA class (P=0.021), lower income (P=0.029), and longer duration of heart failure (P=0.049) were independent predictors of poor HRQOL. CONCLUSION: Depressive symptoms, higher NYHA class, lower income, and longer duration of chronic heart failure are independent predictors of poor HRQOL in elderly patients hospitalized with chronic heart failure in Serbia. Further, there is an association between multiple medication usage and poor HRQOL, as well as a negative impact of cognitive impairment on HRQOL. Hence, measures should be implemented to identify such patients, especially those with depressive symptoms, and appropriate interventions undertaken in order to improve their HRQOL.


Assuntos
Nível de Saúde , Insuficiência Cardíaca/psicologia , Hospitalização , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Depressão , Feminino , Humanos , Masculino , Sérvia , Inquéritos e Questionários
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