CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Williams, Kelly L.; Topp, Simon; Yang, Shu; Smith, Bradley N.; Fifita, Jennifer A.; Warraich, Sadaf T.; Zhang, Katharine Y.; Farrawell, Natalie E.; Vance, Caroline; Hu, Xun; Chesi, Alessandra; Leblond, Claire S.; Lee, Albert; Rayner, Stephanie L.; Sundaramoorthy, Vinod; Dobson‐Stone, Carol; Molloy, Mark P.; Blitterswijk, Marka van; Dickson, Dennis W.; Petersen, Ronald C.; Graff‐Radford, Neill R.; Boeve, Bradley F.; Murray, Melissa E.; Pottier, Cyril; Don, Emily K.; Winnick, Claire; McCann, Emma; Hogan, Alison; Daoud, Hussein; Levert, Annie; Dion, Patrick A.; Mitsui, Jun; Ishiura, Hiroyuki; Takahashi, Yūji; Goto, Jun; Kost, Jason; Gellera, Cinzia; Gkazi, Athina Soragia; Miller, Jack W.; Stockton, Joanne; Brooks, William S.; Boundy, Karyn; Polak, Meraida; Muñoz-Blanco, José Luís; Esteban-Pérez, Jesús; Rábano, Alberto; Hardiman, Orla; Morrison, Karen; Ticozzi, Nicola; Silani, Vincenzo; Belleroche, Jacqueline de; Glass, Jonathan D.; Kwok, John B.; Guillemin, Gilles J.; Chung, Roger S.; Tsuji, Shoji; Brown, Robert H.; García‐Redondo, Alberto; Rademakers, Rosa; Landers, John E.; Gitler, Aaron D.; Rouleau, Guy A.; Cole, Nicholas J.; Yerbury, Justin J.; Atkin, Julie D.; Shaw, Christopher E.; Nicholson, Garth A.; Blair, Ian P.

doi:10.1038/ncomms11253

Cited by 172 publications

(140 citation statements)

References 35 publications

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“…Lastly, in 2016, Williams et al demonstrated the gene CCNF encoding Cyclin F localizing at 16p13.3 is mutated in frontotemporal dementia (Williams et al, 2016). Cyclin F is a component of an E3 ubiquitin–protein ligase complex (SCF CyclinF ) and expression of its mutant form in neuronal cells caused abnormal ubiquitination and accumulation of proteins and subsequent neurodegeneration (Williams et al, 2016). Overall, 16p13.3 is rich in genes which involve in psyhiatric diseases – mainly affective disorders – and genes which may involve in neurodegeneration.…”

Section: Background: New Evidence Suggest That Hemoglobins (Hbs) Are mentioning

confidence: 99%

Hemoglobins emerging roles in mental disorders. Metabolical, genetical and immunological aspects

Altinöz¹,

Ince

2017

Intl J of Devlp Neuroscience

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Hemoglobin (Hb) expression in the central nervous system is recently shown. Cooccurences of mental disorders (mainly bipolar disorder (BD) and tic disorders) with β- or α-thalassemia trait or erythrocytosis were witnessed, which may be due to peripheral or central hypoxia/hyperoxia or haplotypal gene interactions. β-Globin genes reside at 11p15.5 close to tyrosine hydroxylase, dopamine receptor DRD4 and Brain Derived Neurotrophic Factor, which involve in psychiatric diseases. α-Globin genes reside at 16p13.3 which associates with BD, tic disorders, ATR-16 Syndrome and Rubinstein Taybi Syndrome (RTS). CREB-Binding Protein (CEBBP)-gene is mutated in RTS, which commonly associates with mood disorders. 16p13.3 region also contains GRIN2A gene encoding N-methyl-d-aspartate receptor-2A and SSTR5 (Somatostatin Receptor-5), again involving in mental disorders. We demonstrated a protective role of minor HbA2 against post-partum episodes in BD and association of higher minor HbF (fetal hemoglobin) levels with family history of psychosis in a BD-patient cohort. HbA2 increases in cardiac ischemia and in mountain dwellers indicating its likely protection against ischemia/hypoxia. HMGIY, a repressive transcription factor of δ-globin chain of HbA2 is increased in lymphocytes of schizophrenics. In autism, deletional mutations were found in BCL11A gene, which cause persistence of HbF at high levels in adulthood. Also, certain polymorphisms in BCL11A strongly associate with schizophrenia. Further, many drugs from anabolic steroids to antimalarial agents elevate HbF and may cause mania. We ascribe a protective role to HbA2 and a maladaptive detrimental role to HbF in psychopathology. We believe that future studies on hemoglobins may pave to discover novel pathogenesis mechanisms in mental disorders.

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Section: Background: New Evidence Suggest That Hemoglobins (Hbs) Are mentioning

confidence: 99%

Hemoglobins emerging roles in mental disorders. Metabolical, genetical and immunological aspects

Altinöz¹,

Ince

2017

Intl J of Devlp Neuroscience

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“…Genetic studies of ALS patients have revealed that 90% of cases are sporadic (sALS) and the remaining 10% of cases are familial (fALS) (Renton et al, 2014). Several of the fALS associated genes (TDP-43, C9orf72, FUS, ALS2) have roles in the biogenesis and trafficking of RNA species, and another clear grouping are associated with protein degradation (CCNF, VCP, SQSTM1, UBQLN2, OPTN, TBK1); most are also linked to frontotemporal dementia (Cirulli et al, 2015; Peters et al, 2015; Williams et al, 2016). The first fALS linked gene discovered, and most studied, is the gene encoding superoxide dismutase-1 (SOD1) which is only associated with a pure motor neuron disease phenotype.…”

Section: Introductionmentioning

confidence: 99%

Susceptibility of Mutant SOD1 to Form a Destabilized Monomer Predicts Cellular Aggregation and Toxicity but Not In vitro Aggregation Propensity

2016

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the rapid and progressive degeneration of upper and lower motor neurons in the spinal cord, brain stem and motor cortex. The first gene linked to ALS was the gene encoding the free radical scavenging enzyme superoxide dismutase-1 (SOD1) that currently has over 180, mostly missense, ALS-associated mutations identified. SOD1-associated fALS patients show remarkably broad mean survival times (<1 year to ~17 years death post-diagnosis) that are mutation dependent. A hallmark of SOD1-associated ALS is the deposition of SOD1 into large insoluble aggregates in motor neurons. This is thought to be a consequence of mutation induced structural destabilization and/or oxidative damage leading to the misfolding and aggregation of SOD1 into a neurotoxic species. Here we aim to understand the relationship between SOD1 variant toxicity, structural stability, and aggregation propensity using a combination of cell culture and purified protein assays. Cell based assays indicated that aggregation of SOD1 variants correlate closely to cellular toxicity. However, the relationship between cellular toxicity and disease severity was less clear. We next utilized mass spectrometry to interrogate the structural consequences of metal loss and disulfide reduction on fALS-associated SOD1 variant structure. All variants showed evidence of unfolded, intermediate, and compact conformations, with SOD1G37R, SOD1G93A and SOD1V148G having the greatest abundance of intermediate and unfolded SOD1. SOD1G37R was an informative outlier as it had a high propensity to unfold and form oligomeric aggregates, but it did not aggregate to the same extent as SOD1G93A and SOD1V148G in in vitro aggregation assays. Furthermore, seeding the aggregation of DTT/EDTA-treated SOD1G37R with preformed SOD1G93A fibrils elicited minimal aggregation response, suggesting that the arginine substitution at position-37 blocks the templating of SOD1 onto preformed fibrils. We propose that this difference may be explained by multiple strains of SOD1 aggregate and this may also help explain the slow disease progression observed in patients with SOD1G37R.

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“…These genes generally occur in <1% of FALS cases . Among Australian ALS, we have reported rare mutations in UBQLN2 (MIM#300857; NM_013444), CCNF (MIM#600227; NM_001761), TBK1 (MIM#616439; NM_013254), OPTN (MIM#613435 ; NM_001008211) and CREST/SS18L1 (MIM# 606472; NM_198935) …”

Section: Introductionmentioning

confidence: 99%

The genotype–phenotype landscape of familial amyotrophic lateral sclerosis in Australia

et al. 2017

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Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous fatal neurodegenerative disease. Around 10% of ALS cases are hereditary. ALS gene discoveries have provided most of our understanding of disease pathogenesis. We aimed to describe the genetic landscape of ALS in Australia by assessing 1013 Australian ALS patients for known ALS mutations by direct sequencing, whole exome sequencing or repeat primed polymerase chain reaction. Age of disease onset and disease duration were used for genotype-phenotype correlations. We report 60.8% of Australian ALS families in this cohort harbour a known ALS mutation. Hexanucleotide repeat expansions in C9orf72 accounted for 40.6% of families and 2.9% of sporadic patients. We also report ALS families with mutations in SOD1 (13.7%), FUS (2.4%), TARDBP (1.9%), UBQLN2 (.9%), OPTN (.5%), TBK1 (.5%) and CCNF (.5%). We present genotype-phenotype correlations between these genes as well as between gene mutations. Notably, C9orf72 hexanucleotide repeat expansion positive patients experienced significantly later disease onset than ALS mutation patients. Among SOD1 families, p.I114T positive patients had significantly later onset and longer survival. Our report highlights a unique spectrum of ALS gene frequencies among patients from the Australian population, and further, provides correlations between specific ALS mutations with disease onset and/or duration.

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CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Cited by 172 publications

References 35 publications

Hemoglobins emerging roles in mental disorders. Metabolical, genetical and immunological aspects

Hemoglobins emerging roles in mental disorders. Metabolical, genetical and immunological aspects

Susceptibility of Mutant SOD1 to Form a Destabilized Monomer Predicts Cellular Aggregation and Toxicity but Not In vitro Aggregation Propensity

The genotype–phenotype landscape of familial amyotrophic lateral sclerosis in Australia

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