Mutational repeats key factor
This huge study of thousands of cases showed increased risk of motor neurone disease (referred to as ALS in this paper) with increased repeat length of a particular mutation sequence.
A low number of polyalanine repeats in the NIPA1 gene mutation is associated with SPG6 HSP, but more than 8 repeats increases the risk of MND.
NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10-5). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS.
SOURCE: Neurobiol Aging. 2018 Sep 22. pii: S0197-4580(18)30336-1. doi: 10.1016/j.neurobiolaging.2018.09.012. [Epub ahead of print] PMID: 30342764
Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort.
Tazelaar GHP1, Dekker AM1, van Vugt JJFA1, van der Spek RA1, Westeneng HJ1, Kool LJBG1, Kenna KP1, van Rheenen W1, Pulit SL1, McLaughlin RL2, Sproviero W3, Iacoangeli A4, Hübers A5, Brenner D5, Morrison KE6, Shaw PJ7, Shaw CE7, Panadés MP8, Mora Pardina JS9, Glass JD10, Hardiman O11, Al-Chalabi A12, van Damme P13, Robberecht W13, Landers JE14, Ludolph AC5, Weishaupt JH5, van den Berg LH1, Veldink JH1, van Es MA15; Project MinE ALS Sequencing Consortium.
1 Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
2 Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Republic of Ireland.
3 Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King’s College London, London, UK.
4 Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.
5 Department of Neurology, Ulm University, Ulm, Germany.
6 Faculty of Medicine, University of Southampton, Southampton, UK.
7 Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
8 Biomedical Network Research Center on Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Hospitalet de Llobregat, Spain; Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
9 ALS Unit, Hospital San Rafael, Madrid, Spain.
10 Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; Emory ALS Center, Emory University School of Medicine, Atlanta, GA, USA.
11 Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Republic of Ireland; Department of Neurology, Beaumont Hospital, Dublin, Republic of Ireland.
12 Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King’s College London, London, UK; Department of Neurology, King’s College Hospital, London, UK.
13 KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium; VIB, Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
14 Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
15 Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: [email protected]