Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation.

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset, progressive neurodegenerative disorder characterized by tremors, ataxia and neuropsychological problems. This disease is quite common in the general population with approximately 20 million carriers worldwide. The risk of developing FXTAS increases dramatically with age, with about 45% of male carriers over the age of 50 being affected.

A missense variant in the nuclear export signal of the FMR1 gene causes intellectual disability.

Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability and autism spectrum disorders. Mostly, FXS is caused by transcriptional silencing of the FMR1 gene due to a repeat expansion in the 5' UTR, and consequently lack of the protein product FMRP. However, in rare cases FXS is caused by other types of variants in the FMR1 gene.

Refining the Spectrum of Neuronal Intranuclear Inclusion Disease: A Case Report.

Neuronal intranuclear inclusion disease (NIID) is a rare heterogeneous progressive neurodegenerative disease characterized by the presence of eosinophilic hyaline intranuclear inclusions in neuronal and glial cells of the CNS, peripheral cells of the autonomic nervous system, visceral organs and skin. The clinical presentation is broadly heterogeneous and includes limb weakness, dementia, seizures, ataxia, and parkinsonism. High-intensity signal in the corticomedullary junction on brain MRI is a characteristic finding in NIID.

HR23B pathology preferentially co-localizes with p62, pTDP-43 and poly-GA in C9ORF72-linked frontotemporal dementia and amyotrophic lateral sclerosis.

Human homologue of yeast UV excision repair protein Rad23b (HR23B) inclusions are found in a number of neurodegenerative diseases, including frontotemporal dementia (FTD), Huntington's disease (HD), spinocerebellar ataxia type 3 and 7 (SCA3/7), fragile X associated tremor/ataxia syndrome (FXTAS) and Parkinson's disease (PD). Here, we describe HR23B pathology in C9ORF72 linked FTD and amyotrophic lateral sclerosis (ALS) cases. HR23B presented in neuropils, intranuclear inclusions and cytoplasmic and perinuclear inclusions and was predominantly found in cortices (frontal, temporal and motor), spinal cord and hippocampal dentate gyrus.

Astroglial-targeted expression of the fragile X CGG repeat premutation in mice yields RAN translation, motor deficits and possible evidence for cell-to-cell propagation of FXTAS pathology.

The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5'-untranslated region of the fragile X mental retardation 1 (FMR1) gene. Human carriers of the premutation allele are at risk of developing the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Characteristic neuropathology associated with FXTAS includes intranuclear inclusions in neurons and astroglia.

An Integrative Study of Protein-RNA Condensates Identifies Scaffolding RNAs and Reveals Players in Fragile X-Associated Tremor/Ataxia Syndrome.

Recent evidence indicates that specific RNAs promote the formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs). We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly contacted RNAs are structured, have long UTRs, and contain nucleotide repeat expansions.

CXorf56, a dendritic neuronal protein, identified as a new candidate gene for X-linked intellectual disability.

Intellectual disability (ID) comprises a large group of heterogeneous disorders, often without a known molecular cause. X-linked ID accounts for 5-10% of male ID cases. We investigated a large, three-generation family with mild ID and behavior problems in five males and one female, with a segregation suggestive for X-linked inheritance.

Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of Fragile X-associated tremor/ataxia syndrome.

A CGG-repeat expansion in the premutation range in the Fragile X mental retardation 1 gene (FMR1) has been identified as the genetic cause of Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder that manifests with action tremor, gait ataxia and cognitive impairments. In this study, we used a bigenic mouse model, in which expression of a 90CGG premutation tract is activated in neural cells upon doxycycline administration-P90CGG mouse model. We, here, demonstrate the behavioural manifestation of clinically relevant features of FXTAS patients and premutation carrier individuals in this inducible mouse model.

Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of the fragile X-premutation, who have an expanded CGG repeat in the 5'-UTR of the FMR1 gene. FXTAS is characterized by progressive development of intention tremor, ataxia, parkinsonism and neuropsychological problems. The disease is thought to be caused by a toxic RNA gain-of-function mechanism, and the major hallmark of the disease is ubiquitin-positive intranuclear inclusions in neurons and astrocytes.

Induced expression of expanded CGG RNA causes mitochondrial dysfunction in vivo.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation forms of the FMR1 gene, resulting in a progressive development of tremor, ataxia and neuropsychological problems. The disease is caused by an expanded CGG repeat in the FMR1 gene, leading to an RNA gain-of-function toxicity mechanism. In order to study the pathogenesis of FXTAS, new inducible transgenic mouse models have been developed that expresses either 11CGGs or 90CGGs at the RNA level under control of a Tet-On promoter.

FMRpolyG-positive inclusions in CNS and non-CNS organs of a fragile X premutation carrier with fragile X-associated tremor/ataxia syndrome.

Unlabelled: para

Electronic Supplementary Material: The online version of this article (doi:10.1186/s40478-014-0162-2) contains supplementary material, which is available to authorized users.

PRKAR1B mutation associated with a new neurodegenerative disorder with unique pathology.

Pathological accumulation of intermediate filaments can be observed in neurodegenerative disorders, such as Alzheimer's disease, frontotemporal dementia and Parkinson's disease, and is also characteristic of neuronal intermediate filament inclusion disease. Intermediate filaments type IV include three neurofilament proteins (light, medium and heavy molecular weight neurofilament subunits) and α-internexin. The phosphorylation of intermediate filament proteins contributes to axonal growth, and is regulated by protein kinase A.

Exome sequencing and functional analyses suggest that SIX6 is a gene involved in an altered proliferation-differentiation balance early in life and optic nerve degeneration at old age.

Primary open-angle glaucoma (POAG) is a hereditary neurodegenerative disease, characterized by optic nerve changes including increased excavation, notching and optic disc hemorrhages. The excavation can be described by the vertical cup-disc ratio (VCDR). Previously, genome-wide significant evidence for the association of rs10483727 in SIX1-SIX6 locus with VCDR and subsequent POAG was found.

FBXO7 immunoreactivity in α-synuclein-containing inclusions in Parkinson disease and multiple system atrophy.

Mutations in the gene encoding the F-box only protein 7 (FBXO7) cause PARK15, an autosomal recessive form of juvenile parkinsonism. Although the brain pathology in PARK15 patients remains unexplored, in vivo imaging displays severe loss of nigrostriatal dopaminergic terminals. Understanding the pathogenesis of PARK15 might therefore illuminate the mechanisms of the selective dopaminergic neuronal degeneration, which could also be important for understanding idiopathic Parkinson disease (PD).

Dopaminergic neuronal loss and dopamine-dependent locomotor defects in Fbxo7-deficient zebrafish.

Recessive mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, a mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by FBXO7, and the pathogenesis of PARK15 remain unknown. No animal models of this disease exist.

NPHP4 variants are associated with pleiotropic heart malformations.

Rationale: Congenital heart malformations are a major cause of morbidity and mortality, especially in young children. Failure to establish normal left-right (L-R) asymmetry often results in cardiovascular malformations and other laterality defects of visceral organs.

Objective: To identify genetic mutations causing cardiac laterality defects.

Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease.

Manganese is essential for several metabolic pathways but becomes toxic in excessive amounts. Manganese levels in the body are therefore tightly regulated, but the responsible protein(s) remain incompletely known. We studied two consanguineous families with neurologic disorders including juvenile-onset dystonia, adult-onset parkinsonism, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis.

Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder generally presenting with intention tremor and gait ataxia, but with a growing list of co-morbid medical conditions including hypothyroidism, hypertension, peripheral neuropathy, and cognitive decline. The pathological hallmark of FXTAS is the presence of intranuclear inclusions in both neurons and astroglia. However, it is unknown to what extent such inclusions are present outside the central nervous system (CNS).

Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).

Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized.

Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis.

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis.