NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Kenna, Kevin P.; Doormaal, Perry T C van; Dekker, Annelot M.; Ticozzi, Nicola; Kenna, Brendan; Diekstra, Frank P.; Rheenen, Wouter van; Eijk, Kristel R. van; Jones, Ashley; Keagle, Pamela; Shatunov, Aleksey; Sproviero, William; Smith, Bradley N.; Es, Michael A. van; Topp, Simon; Kenna, Aoife; Miller, Jack W.; Fallini, Claudia; Tiloca, Cinzia; McLaughlin, Russell L.; Vance, Caroline; Troakes, Claire; Colombrita, Claudia; Mora, Gabriele; Calvo, Andrea; Verde, Federico; Al‐Sarraj, Safa; King, Andrew; Calini, Daniela; Belleroche, Jacqueline de; Baas, Frank; Kooi, Anneke J. van der; Visser, Marjolein; Asbroek, Anneloor L.M.A. ten; Sapp, Peter C.; McKenna‐Yasek, Diane; Polak, Meraida; Asress, Seneshaw; Muñoz-Blanco, José Luís; Strom, Tim M.; Meitinger, Thomas; Morrison, Karen; Lauria, Giuseppe; Williams, Kelly L.; Leigh, P. Nigel; Nicholson, Garth A.; Blair, Ian P.; Leblond, Claire S.; Dion, Patrick A.; Rouleau, Guy A.; Pall, Hardev; Shaw, Pamela J.; Turner, Martin R; Talbot, Kevin; Taroni, Franco; Boylan, Kevin B.; Blitterswijk, Marka van; Rademakers, Rosa; Esteban-Pérez, Jesús; García‐Redondo, Alberto; Damme, Philip Van; Robberecht, Wim; Chiò, Adriano; Gellera, Cinzia; Drepper, Carsten; Sendtner, Michael; Ratti, Antonia; Glass, Jonathan D.; Mora, Jesús; Başak, Nazlı; Hardiman, Orla; Ludolph, Albert C.; Andersen, Peter M.; Weishaupt, Jochen H.; Brown, Robert H.; Al‐Chalabi, Ammar; Silani, Vincenzo; Shaw, Christopher E.; Berg, Leonard H van den; Veldink, Jan H.; Landers, John E.

doi:10.1038/ng.3626

Cited by 232 publications

(202 citation statements)

References 52 publications

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“…Afterwards, it was identified that a significant association of rs10463311 spanning GPX3-TNIP1 with ALS in the meta analysis of GWAS data from Chinese and European cohorts (Benyamin et al, 2017). Recently, NEK1 was reported a risk ALS gene based on the meta-analysis of WES data from large cohorts of Chinese and European ancestry (Gratten et al, 2017), which was consistent with the two studies from several European countries (Brenner et al, 2016; Kenna et al, 2016) and considered the first study to define a new gene with WES data in Chinese ALS.…”

Section: Genetic Characteristics Of Chinese Als Patientssupporting

confidence: 64%

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

Liu

Gao

et al. 2018

Brain Research

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with loss of motor neurons. Previous knowledge of the disease has been mainly based on studies from Caucasian ALS patients of European descent. Here we review the epidemiological characteristics of ALS among the Chinese population in order to compare the similarities and differences between Chinese ALS cases and those from other countries. We describe a potential lower incidence and prevalence of ALS, a younger age of onset and a lower proportion of familial ALS cases in the Chinese population. Additionally, we highlight potential genetic differences between Chinese and Caucasian ALS patients. Most notably, the frequency of GGGGCC repeat expansions in C9ORF72 in Chinese ALS is significantly lower than in Caucasians. Since some conclusions might not be consistent across all of the studies around China to date, we suggest that it is necessary to carry out a prospective population-based study and large-scale gene sequencing around to better define epidemiological and genetic features of Chinese ALS patients.

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Section: Genetic Characteristics Of Chinese Als Patientssupporting

confidence: 64%

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

Liu

Gao

et al. 2018

Brain Research

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“…Thus, besides cosegregation data, we put emphasis on the low frequency of specific variants for our classification, based on the observation that rare and unique alleles contribute most to the heritability of ALS,61 and known monogenic causes of familial ALS represent mostly rare or even private mutations. One exception was principally made for loss-of-function variants in NEK1 with an MAF above 1:10 000, as NEK1 variants have a greatly reduced penetrance,62 although loss-of-function variants in NEK1 were lacking in our German fALS cohort. The second exception is the known pathogenic p.D91A mutation with an MAF of 1:891.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive analysis of the mutation spectrum in 301 German ALS families

Müller

Brenner

Weydt

et al. 2018

J Neurol Neurosurg Psychiatry

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“…In a recent exome-wide study, the mutation of a gene that encodes the serine/threonine kinase NIMA (never in mitosis gene-A)-related kinase, NEK1, was found in~ 3% of ALS cases in European and European-American families (Kenna et al, 2016). It is worth to note that NEK1 is an established DNA damage response factor,(Chen et al, 2011)further studies may needed to focus on NEK1 mutation mediated DNA damage repair deficiency in in ALS pathology.…”

Section: Introductionmentioning

confidence: 99%

TDP-43/FUS in motor neuron disease: Complexity and challenges

Guerrero

Wang

Mitra

et al. 2016

Progress in Neurobiology

107

122

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Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.

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NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Cited by 232 publications

References 52 publications

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

Comprehensive analysis of the mutation spectrum in 301 German ALS families

TDP-43/FUS in motor neuron disease: Complexity and challenges

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