Chromosome 9 Teases With Cryptic ALS/FTLD Link

Somewhere on the short arm of the ninth chromosome, there lies a locus, or loci, that can cause amyotrophic lateral sclerosis (ALS) or frontotemporal lobar dementia (FTLD). A portion of the petit (p) arm has come up again and again in genome scans, but the exact variant has proved difficult to identify. In this month’s Archives of Neurology, researchers from VIB-University of Antwerp, Belgium, report on a large family that passed a chromosome 9p variant along to members with one or the other condition. The scientists also found evidence for a novel locus on chromosome 14 that may interact with the 9p variant to produce disease. Study authors included first author Ilse Gijselinck and senior authors Marc Cruts and Christine Van Broeckhoven. “This is one more chromosome 9 family in a row of several families,” said senior author Marc Cruts. “It stresses—again—the importance of this region and the gene that is going to be found in this region.”

The researchers came to the four-generation Belgian family via a man with FTLD. Among 29 family members in the study, nine were affected: two had FTLD; four had unspecified dementia; two had dementia with parkinsonism and one had ALS. (A further two family members had some symptoms associated with ALS, such as low muscle strength, but were never diagnosed with the disease.)

Cruts and colleagues scanned the DNA of these relatives for loci that co-segregated with any of these conditions. Their studies pointed to a region of chromosome 9 and, with near-statistical significance, one on chromosome 14. The researchers sequenced the coding portions of 73 candidate genes in the two regions but were unable to find specific variants that were present only in affected family members and not in controls within the family or in the general population.

“I think everyone will agree that there is some genetic variant at 9p that influences ALS and dementia,” wrote Michael van Es of University Medical Center Utrecht in The Netherlands, who was not involved with the latest study, in an e-mail to ARF. Multiple analyses have pointed to that part of the genome (see ARF related news story on van Es et al., 2009; Luty et al., 2008; Valdmanis et al., 2007; Vance et al., 2006). Between the current and past studies, researchers have sequenced all the amino acid-encoding DNA in the suspect region, Cruts said, so now they must start looking for non-coding variants. For example, he suggested, a variant in a regulatory region could cause disease.

Another possibility is that the variant is due to an inversion, insertion, or deletion. The genome sequencing technique Cruts and colleagues used—comparative genomic hybridization—is likely to miss these chromosomal abnormalities if they are less than 1 kilobase in length. The researchers are taking two approaches to find those kinds of variants. “We are using the very old-fashioned and the next-generation technologies,” he said. The old-fashioned is restriction fragment length analysis, which can identify, from fragments that are too short or too long, missing or excess DNA. The second approach is next-generation DNA sequencing—faster, but also more expensive—that will allow the scientists to sequence the region with higher resolution so they can discover small changes.

The chromosome 9 locus, having popped up in so many studies, appears to be a fairly solid lead. This paper is the first, however, to point to chromosome 14. Each affected person in the family carried both chromosome variants, according to the study. That suggests they might work in tandem somehow. For example, the body might be able to function properly with variation at just one locus, but not at both. Or perhaps, Cruts suggested, one variant affects a gene that modifies a gene at the other locus. In support of these hypotheses, one family member carried only the chromosome 9 variant—and was not sick. It is also possible, Cruts conceded, that the chromosome 14 link is simply a false-positive match that will not be confirmed in other studies.

These genetic variants, whatever they may be, cause a diverse set of symptoms in affected individuals. However, the diversity of conditions fits well with an idea, supported by many researchers, that ALS and FTLD lie at opposite ends of a spectrum of disorders (Geser et al., 2009). The two conditions are linked by TDP-43 proteinopathy, which was evident in the single member of the Belgian family whose autopsy tissue was available. Cruts suspects that the diseases in this family are the same pathology at different parts of the nervous system, and suggested that other variation in a person’s genes may determine whether the brain, spinal cord, or both are affected.—Amber Dance

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References

News Citations

  1. Research Brief: Latest ALS GWAS Points to Loci on Chromosomes 9, 19

Paper Citations

  1. van Es MA, Veldink JH, Saris CG, Blauw HM, van Vught PW, Birve A, Lemmens R, Schelhaas HJ, Groen EJ, Huisman MH, van der Kooi AJ, de Visser M, Dahlberg C, Estrada K, Rivadeneira F, Hofman A, Zwarts MJ, van Doormaal PT, Rujescu D, Strengman E, Giegling I, Muglia P, Tomik B, Slowik A, Uitterlinden AG, Hendrich C, Waibel S, Meyer T, Ludolph AC, Glass JD, Purcell S, Cichon S, Nöthen MM, Wichmann HE, Schreiber S, Vermeulen SH, Kiemeney LA, Wokke JH, Cronin S, McLaughlin RL, Hardiman O, Fumoto K, Pasterkamp RJ, Meininger V, Melki J, Leigh PN, Shaw CE, Landers JE, Al-Chalabi A, Brown RH Jr, Robberecht W, Andersen PM, Ophoff RA, van den Berg LH. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009 Oct;41(10):1083-7. Epub 2009 Sep 6 PubMed.
  2. Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT, Dobson-Stone C, Panegyres PK, Hecker J, Nicholson GA, Halliday GM, Schofield PR. Pedigree with frontotemporal lobar degeneration--motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9. BMC Neurol. 2008;8:32. PubMed.
  3. Valdmanis PN, Dupre N, Bouchard JP, Camu W, Salachas F, Meininger V, Strong M, Rouleau GA. Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. Arch Neurol. 2007 Feb;64(2):240-5. PubMed.
  4. Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, Siddique T, Schelhaas HJ, Kusters B, Troost D, Baas F, de Jong V, Shaw CE. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain. 2006 Apr;129(Pt 4):868-76. PubMed.
  5. Geser F, Martinez-Lage M, Kwong LK, Lee VM, Trojanowski JQ. Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J Neurol. 2009 Aug;256(8):1205-14. PubMed.

Further Reading

Papers

  1. Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010 May 13;465(7295):223-6. PubMed.
  2. Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M, Arnold SE, Mann DM, Pickering-Brown SM, Seelaar H, Heutink P, van Swieten JC, Murrell JR, Ghetti B, Spina S, Grafman J, Hodges J, Spillantini MG, Gilman S, Lieberman AP, Kaye JA, Woltjer RL, Bigio EH, Mesulam M, Al-Sarraj S, Troakes C, Rosenberg RN, White CL, Ferrer I, Lladó A, Neumann M, Kretzschmar HA, Hulette CM, Welsh-Bohmer KA, Miller BL, Alzualde A, Lopez de Munain A, McKee AC, Gearing M, Levey AI, Lah JJ, Hardy J, Rohrer JD, Lashley T, Mackenzie IR, Feldman HH, Hamilton RL, Dekosky ST, van der Zee J, Kumar-Singh S, Van Broeckhoven C, Mayeux R, Vonsattel JP, Troncoso JC, Kril JJ, Kwok JB, Halliday GM, Bird TD, Ince PG, Shaw PJ, Cairns NJ, Morris JC, McLean CA, Decarli C, Ellis WG, Freeman SH, Frosch MP, Growdon JH, Perl DP, Sano M, Bennett DA, Schneider JA, Beach TG, Reiman EM, Woodruff BK, Cummings J, Vinters HV, Miller CA, Chui HC, Alafuzoff I, Hartikainen P, Seilhean D, Galasko D, Masliah E, Cotman CW, Tuñón MT, Martínez MC, Munoz DG, Carroll SL, Marson D, Riederer PF, Bogdanovic N, Schellenberg GD, Hakonarson H, Trojanowski JQ, Lee VM. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010 Mar;42(3):234-9. PubMed.
  3. Chiò A, Schymick JC, Restagno G, Scholz SW, Lombardo F, Lai SL, Mora G, Fung HC, Britton A, Arepalli S, Gibbs JR, Nalls M, Berger S, Kwee LC, Oddone EZ, Ding J, Crews C, Rafferty I, Washecka N, Hernandez D, Ferrucci L, Bandinelli S, Guralnik J, Macciardi F, Torri F, Lupoli S, Chanock SJ, Thomas G, Hunter DJ, Gieger C, Wichmann HE, Calvo A, Mutani R, Battistini S, Giannini F, Caponnetto C, Mancardi GL, La Bella V, Valentino F, Monsurrò MR, Tedeschi G, Marinou K, Sabatelli M, Conte A, Mandrioli J, Sola P, Salvi F, Bartolomei I, Siciliano G, Carlesi C, Orrell RW, Talbot K, Simmons Z, Connor J, Pioro EP, Dunkley T, Stephan DA, Kasperaviciute D, Fisher EM, Jabonka S, Sendtner M, Beck M, Bruijn L, Rothstein J, Schmidt S, Singleton A, Hardy J, Traynor BJ. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2009 Apr 15;18(8):1524-32. PubMed.
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  5. Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006 Sep;7(9):710-23. PubMed.
  6. Mitchell J, Paul P, Chen HJ, Morris A, Payling M, Falchi M, Habgood J, Panoutsou S, Winkler S, Tisato V, Hajitou A, Smith B, Vance C, Shaw C, Mazarakis ND, de Belleroche J. Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7556-61. PubMed.

Primary Papers

  1. Gijselinck I, Engelborghs S, Maes G, Cuijt I, Peeters K, Mattheijssens M, Joris G, Cras P, Martin JJ, De Deyn PP, Kumar-Singh S, Van Broeckhoven C, Cruts M. Identification of 2 Loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol. 2010 May;67(5):606-16. PubMed.

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