Assuntos
Regiões 3' não Traduzidas/genética , Colágeno Tipo IV/genética , Demência por Múltiplos Infartos/genética , Saúde da Família , Predisposição Genética para Doença/genética , Mutação/genética , Demência por Múltiplos Infartos/fisiopatologia , Feminino , Estudos de Associação Genética , Células HEK293 , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Suécia , TransfecçãoRESUMO
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia. Our aim was to clarify the genetic background of dementia in this cohort by analysing both known dementia-associated genes (APOE, APP, C9ORF72, GRN, PSEN1 and PSEN2) and searching for rare or novel segregating variants with exome sequencing. C9orf72 repeat expansions were detected in 12 (20%) of the 60 families, including, in addition to FTD, a family with neuropathologically verified AD. Twelve families (10 with AD and 2 with FTD) with representative samples from affected and unaffected subjects and without C9orf72 expansions were selected for whole-exome sequencing. Exome sequencing did not reveal any variants that could be regarded unequivocally causative, but revealed potentially damaging variants in UNC13C and MARCH4.
Assuntos
Doença de Alzheimer/genética , Proteína C9orf72/genética , Demência Frontotemporal/genética , Predisposição Genética para Doença , Idoso , Doença de Alzheimer/patologia , Feminino , Demência Frontotemporal/patologia , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Sequenciamento do ExomaRESUMO
Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia. Gene expression studies showed decreased GRN gene expression in mutation carriers' blood samples. In conclusion, we describe a novel GRN, p.(Tyr229*) mutation, resulting in haploinsufficiency of GRN and a severe neuropathologic FTLD phenotype.
Assuntos
Encéfalo/patologia , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Proteínas de Ligação a DNA/metabolismo , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Progranulinas , RNA Mensageiro/metabolismo , Tirosina/genéticaRESUMO
CADASIL and CARASIL are hereditary small vessel diseases leading to vascular dementia. CADASIL commonly begins with migraine followed by minor strokes in mid-adulthood. Dominantly inherited CADASIL is caused by mutations (n > 230) in NOTCH3 gene, which encodes Notch3 receptor expressed in vascular smooth muscle cells (VSMC). Notch3 extracellular domain (N3ECD) accumulates in arterial walls followed by VSMC degeneration and subsequent fibrosis and stenosis of arterioles, predominantly in cerebral white matter, where characteristic ischemic MRI changes and lacunar infarcts emerge. The likely pathogenesis of CADASIL is toxic gain of function related to mutation-induced unpaired cysteine in N3ECD. Definite diagnosis is made by molecular genetics but is also possible by electron microscopic demonstration of pathognomonic granular osmiophilic material at VSMCs or by positive immunohistochemistry for N3ECD in dermal arteries. In rare, recessively inherited CARASIL the clinical picture and white matter changes are similar as in CADASIL, but cognitive decline begins earlier. In addition, gait disturbance, low back pain and alopecia are characteristic features. CARASIL is caused by mutations (presently n = 10) in high-temperature requirement. A serine peptidase 1 (HTRA1) gene, which result in reduced function of HTRA1 as repressor of transforming growth factor-ß (TGF ß) -signaling. Cerebral arteries show loss of VSMCs and marked hyalinosis, but not stenosis.
Assuntos
Alopecia/genética , Alopecia/patologia , CADASIL/genética , CADASIL/patologia , Infarto Cerebral/genética , Infarto Cerebral/patologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Doenças da Coluna Vertebral/genética , Doenças da Coluna Vertebral/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , HumanosRESUMO
We describe the clinical, neuropathological, and genetic features of a Finnish patient with a novel α-synuclein (SNCA) mutation A53E. The patient was clinically diagnosed with atypical Parkinson's disease (PD) with age of onset at 36 years. In the neuropathological analysis performed at the age of 60 years, highly abundant SNCA pathology was observed throughout the brain and spinal cord showing features of multiple system atrophy and PD. Neuronal and glial (including oligodendroglial) SNCA inclusions and neurites were found to be particularly prominent in the putamen, caudatus, amygdala, temporal and insular cortices, gyrus cinguli, and hippocampus CA2-3 region. These areas as well as the substantia nigra and locus coeruleus showed neuronal loss and gliosis. We also found TDP-43 positive but mostly SNCA negative perinuclear inclusions in the dentate fascia of the hippocampus. The A53E mutation was found in 2 other relatives who had parkinsonism. Our results suggest that the novel SNCA A53E substitution is a causative mutation resulting clinically in parkinsonism and pathologically in severe multiple system atrophy- and PD-type phenotype.
Assuntos
Estudos de Associação Genética , Atrofia de Múltiplos Sistemas/genética , Mutação , Doença de Parkinson/genética , alfa-Sinucleína/genética , Adulto , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/patologia , Neuritos/metabolismo , Doença de Parkinson/patologia , Linhagem , Fenótipo , Medula Espinal/metabolismo , Medula Espinal/patologia , alfa-Sinucleína/metabolismoRESUMO
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary vascular dementia caused by mutations in NOTCH3 gene. Pathology is manifested in small- and middle-sized arteries throughout the body, though primarily in cerebral white matter. Hemodynamics is altered in CADASIL and NOTCH3 is suggested to regulate actin filament polymerization and thereby vascular tone. We analyzed NOTCH3 expression and morphology of actin cytoskeleton in genetically genuine cultured human CADASIL vascular smooth muscle cells (VSMCs) (including a cell line homozygous for p.Arg133Cys mutation) derived from different organs, and in control VSMCs with short hairpin RNA (shRNA)-silenced NOTCH3. NOTCH3 protein level was higher in VSMCs derived from adult than newborn arteries in both CADASIL and control VSMCs. CADASIL VSMCs showed altered actin cytoskeleton including increased branching and node formation, and more numerous and smaller adhesion sites than control VSMCs. Alterations in actin cytoskeleton in shRNA-silenced VSMCs were similar as in CADASIL VSMCs. Severity of the alterations in actin filaments corresponded to NOTCH3 expression level being most severe in VSMCs derived from adult cerebral arteries. These observations suggest that hypomorphic NOTCH3 activity causes alterations in actin organization in CADASIL. Furthermore, arteries from different organs have specific characteristics, which modify the effects of the NOTCH3 mutation and which is one explanation for the exceptional susceptibility of cerebral white matter arteries.