Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS

Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.

[1]  C. van Broeckhoven,et al.  Identification of 2 Loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. , 2010, Archives of neurology.

[2]  C. Duijn,et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 , 2006, Nature.

[3]  C. Iadecola,et al.  Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice , 2010, The Journal of experimental medicine.

[4]  P. Jin,et al.  RNA-Binding Proteins hnRNP A2/B1 and CUGBP1 Suppress Fragile X CGG Premutation Repeat-Induced Neurodegeneration in a Drosophila Model of FXTAS , 2007, Neuron.

[5]  Ewout J N Groen,et al.  Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis , 2009, Nature Genetics.

[6]  B. Byrne,et al.  Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy , 2000, The EMBO journal.

[7]  P. Schofield,et al.  Pedigree with frontotemporal lobar degeneration – motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9 , 2008, BMC neurology.

[8]  J L Haines,et al.  Supporting Online Material Materials and Methods Figs. S1 to S7 Tables S1 to S4 References Mutations in the Fus/tls Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis , 2022 .

[9]  B. Boeve,et al.  Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[10]  H. Zoghbi,et al.  Inactivation of hnRNP K by Expanded Intronic AUUCU Repeat Induces Apoptosis Via Translocation of PKCδ to Mitochondria in Spinocerebellar Ataxia 10 , 2010, PLoS genetics.

[11]  Catherine Lomen-Hoerth,et al.  The overlap of amyotrophic lateral sclerosis and frontotemporal dementia , 2002, Neurology.

[12]  V. Meininger,et al.  Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. , 2007, Archives of neurology.

[13]  A. Farmer,et al.  Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study , 2010, The Lancet Neurology.

[14]  E. Anderson.  Hudson et al. , 1977 .

[15]  S. Naylor,et al.  Myotonic Dystrophy Type 2 Caused by a CCTG Expansion in Intron 1 of ZNF9 , 2001, Science.

[16]  Weimin Sun,et al.  Qualitative assessment of FMR1 (CGG)n triplet repeat status in normal, intermediate, premutation, full mutation, and mosaic carriers in both sexes: Implications for fragile X syndrome carrier and newborn screening , 2010, Genetics in Medicine.

[17]  David E. Housman,et al.  Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member , 1992, Cell.

[18]  N. Graff-Radford,et al.  FRONTOTEMPORAL DEMENTIA , 2004, Seminars in neurology.

[19]  R. Faber,et al.  Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. , 1999, Neurology.

[20]  M. Nalls,et al.  The chromosome 9 ALS and FTD locus is probably derived from a single founder , 2012, Neurobiology of Aging.

[21]  D. Cleveland,et al.  TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. , 2010, Human molecular genetics.

[22]  David Heckerman,et al.  A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD , 2011, Neuron.

[23]  E. Buratti,et al.  TDP-43 Binds Heterogeneous Nuclear Ribonucleoprotein A/B through Its C-terminal Tail , 2005, Journal of Biological Chemistry.

[24]  D. Hernandez,et al.  Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p , 2011, Journal of Neurology.

[25]  Yuko Saito,et al.  Spinocerebellar ataxia type 31 is associated with "inserted" penta-nucleotide repeats containing (TGGAA)n. , 2009, American journal of human genetics.

[26]  C. Amemiya,et al.  Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. , 1992, Science.

[27]  M. Cynader,et al.  Progranulin deficiency leads to enhanced cell vulnerability and TDP-43 translocation in primary neuronal cultures , 2010, Brain Research.

[28]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[29]  Bruce L. Miller,et al.  Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis , 2006, Science.

[30]  D. Nelson,et al.  Evidence for RNA-mediated toxicity in the fragile X-associated tremor/ataxia syndrome. , 2009, Future neurology.

[31]  Peter K. Todd,et al.  RNA‐mediated neurodegeneration in repeat expansion disorders , 2009, Annals of neurology.

[32]  Orla Hardiman,et al.  Cognitive impairment in amyotrophic lateral sclerosis , 2007, The Lancet Neurology.

[33]  Koji Abe,et al.  Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. , 2011, American journal of human genetics.

[34]  T. Ebner,et al.  RNA Gain-of-Function in Spinocerebellar Ataxia Type 8 , 2009, PLoS genetics.

[35]  Michael Q. Zhang,et al.  An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers. , 2006, Human molecular genetics.

[36]  K. Talbot,et al.  The role of RNA processing in the pathogenesis of motor neuron degeneration , 2010, Expert Reviews in Molecular Medicine.

[37]  David Heckerman,et al.  Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study , 2010, The Lancet Neurology.

[38]  M. Freedman,et al.  Frontotemporal lobar degeneration , 1998, Neurology.

[39]  J. Trojanowski,et al.  Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations , 2008, Acta Neuropathologica.

[40]  M. J. Fresnadillo Martínez,et al.  Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions , 2010, Nature Genetics.

[41]  Guy A Rouleau,et al.  Genetics of familial and sporadic amyotrophic lateral sclerosis. , 2006, Biochimica et biophysica acta.

[42]  P. Hagerman,et al.  FMR1 RNA within the Intranuclear Inclusions of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) , 2004, RNA biology.

[43]  L. Petrucelli,et al.  Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. , 2010, The American journal of pathology.

[44]  S. Heath,et al.  Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease , 2009, Neurology.

[45]  Xun Hu,et al.  Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6 , 2009, Science.

[46]  Jinhua Wang,et al.  ESEfinder: a web resource to identify exonic splicing enhancers , 2003, Nucleic Acids Res..

[47]  F. Baas,et al.  Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. , 2006, Brain : a journal of neurology.

[48]  T. Ebner,et al.  Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8 , 2006, Nature Genetics.

[49]  H. Horvitz,et al.  A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia , 2006, Neurology.

[50]  B. Miller,et al.  Are amyotrophic lateral sclerosis patients cognitively normal? , 2003, Neurology.

[51]  M. Swanson,et al.  Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. , 1996, Nucleic acids research.

[52]  Xun Hu,et al.  TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis , 2008, Science.

[53]  A. Naldi,et al.  Dementia and cognitive impairment in amyotrophic lateral sclerosis: a review , 2011, Neurological Sciences.

[54]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[55]  J. Trojanowski,et al.  Pathological TDP‐43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations , 2007, Annals of neurology.

[56]  B. McConkey,et al.  TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis , 2008, Nature Genetics.