Massive ALS GWAS Cements Cytoskeletal Link to Disease

March 28, 2018 - als

A genome-wide organisation investigate for common gene variants and for singular mutations incriminates a microtubule engine protein in amyotrophic parallel sclerosis (ALS). The large general partnership spearheaded by John Landers of a University of Massachusetts Medical School in Worcester and Bryan Traynor of a National Institute on Aging in Bethesda, Maryland, identified a common missense various and several singular loss-of-function (LOF) mutations in a kinesin family member 5A (KIF5A). It strengthens a evidence that perturbations in cytoskeletal duty play an critical purpose in ALS, and offers a intensity aim for drug development. Six co-first authors, 200-plus delegate authors, and 9 consortia collaborated to genotype scarcely 100,000 subjects, including 25,000 with ALS. This largest ALS GWAS to date was published Mar 21 in Neuron.

KIF5A has been on a radar for a while. It popped adult as an ALS claimant gene in several prior analyses, though never reached genome-wide stress (Kenna et al., 2016). That altered when initial authors Aude Nicolas, Alan Renton, Faraz Fagrhi, and Ruth Chia during NIH genotyped singular nucleotide polymorphisms (SNPs) among 20,806 people with ALS and 59,084 controls. They unclosed 5 SNPs travelling several hundred kilobases on chromosome 12 that achieved genome-wide significance. Four occurred in noncoding DNA, with a fifth alighting in a coding segment for KIF5A, changing a proline during position 986 to a leucine. The leucine various increasing a risk of ALS a medium 1.38-fold. The organisation hold adult in an eccentric riposte set and in a meta-analysis of total genotyping information from 103,549 people. The GWAS also reliable 5 formerly identified ALS risk genes: TNP1, C9ORF72, TBK1, UNC13A, and C21ORF2.

Kevin Kenna and Nicola Ticozzi in Landers’ organisation took a opposite hook by examining exome method information from patrimonial ALS cases, acid for genes with suddenly high rates of loss-of-function (LOF) mutations that compared with a disease. In prior work, they and others used a same rare-variant research to brand TBK1 and NEK1 mutations that means patrimonial ALS (Feb 2015 news; Aug 2016 news). In a new study, that examined exomes of 1,138 patrimonial cases and 19,494 controls, 3 genes achieved genome-wide significance: TBK1, NEK1, and KIF5A. Loss-of-function mutations in KIF5A increasing a risk of ALS 40-fold.

In all, Landers’ group identified 12 disease-associated mutations, all clustered during a splice junctions of exon 27 in a C-terminal segment of a gene. The investigators likely that these changes would means exon skipping and a reading-frame change, altering a C depot peptide method and unfortunate a protein’s function. They reliable divergent KIF5A splicing in blood cells from dual patients with opposite mutations, in agreement with new work from Joachim Weishaupt’s lab in Ulm, Germany (Brenner et al., 2018). They did not magnitude protein function.

KIF5A mutations caused an early onset, solemnly surpassing form of ALS, a researchers found. The normal ALS studious notices symptoms during about age 65 and survives only 20–36 months. People with KIF5A LOF mutations got ill in their 40s, though survived for scarcely 10 years.

How do a mutations means ALS? Neurons count on KIF5A for microtubule-dependent axonal ride of organelles, that falters in ALS. KIF5A knockout mice remove a ability to convey mitochondria adult and down axons in engine neurons (Karle et al., 2012). Researchers have documented identical defects in ALS rodent models, and also in engine neurons subsequent from people carrying variants in a FUS gene that means ALS (Oct 2017 news). Besides mitochondria, KIF5A transports other cargoes concerned in ALS, including RNA-containing granules harboring FUS and another RNA-binding protein, hnRNPA1.

Interestingly, mutations in a N-terminus of a protein means dual other patrimonial neuropathies: patrimonial spastic paraplegia (SPG10) and Charcot-Marie-Tooth illness form 2 (CMT2). Now, it appears that C-terminal mutations give arise to a third, graphic outcome: ALS. “Seeing mutations in opposite domains that give opposite diseases—that was really surprising,” Landers told Alzforum. KIF5A’s N-terminal codes for a engine domain that contacts microtubules, while a C-terminus binds cargo. The authors assume that detriment of engine activity contra load contracting could block axonal ride in graphic ways, heading to opposite patterns of neurodegeneration.

No Overlap. Mutations in a cargo-binding tail of KIF5A means ALS, while changes in a microtubule-binding and petiole domains means a patrimonial marginal neuropathies SPG10 and CMT2. [Courtesy of Nicolas et al., Neuron 2018.]

KIF5A joins a handful of other ALS genes concerned in cytoskeletal dynamics, including profilin, TUBA4A, neurofilament, peripherin, and NEK1 (Jul 2012 news; Oct 2014 news; Al-Chalibi et al., 1999; Gros-Louis et al., 2004). Together, they prominence this complement as a intensity source for healing targets. Landers told Alzforum his lab members are focusing their efforts on building novel rodent models, and genetic and chemical screens formed on KIF5A and other cytoskeletal genes they have unclosed (Oct 2016 news).—Pat McCaffrey

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News Citations

  1. TANK-Binding Kinase 1 Rumbles in as New ALS Gene 20 Feb 2015
  2. Genetic Studies Uncover Four New ALS Genes 4 Aug 2016
  3. Mutant FUS Jams Axons, Blocking a Deacetylase May Help 27 Oct 2017
  4. Profilin Gene Is Actin’ in ALS 13 Jul 2012
  5. Novel Exome Screen Points to Tubulin as ALS Gene 25 Oct 2014
  6. Profilin 1 Mutant Mouse—a New Model for ALS? 7 Oct 2016

Paper Citations

  1. .
    NEK1 variants consult ionization to amyotrophic parallel sclerosis.
    Nat Genet. 2016 Sep;48(9):1037-42. Epub 2016 Jul 25
  2. .
    Hot-spot KIF5A mutations means patrimonial ALS.
    Brain. 2018 Jan 12;
  3. .
    Axonal ride necessity in a KIF5A( -/- ) rodent model.
    Neurogenetics. 2012 May;13(2):169-79. Epub 2012 Apr 1
  4. .
    Deletions of a complicated neurofilament subunit tail in amyotrophic parallel sclerosis.
    Hum Mol Genet. 1999 Feb;8(2):157-64.
  5. .
    A frameshift deletion in peripherin gene compared with amyotrophic parallel sclerosis.
    J Biol Chem. 2004 Oct 29;279(44):45951-6.

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