The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder

Publikation

The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder

Wissenschaftlicher Artikel/Review - 13.06.2012

Shaw Christopher E, Shaw Pamela J, Robberecht Wim, Van Damme Phillip, Veldink Jan, Van den Berg Leonard, Ticozzi Nicola, Taroni Franco, Gellera Cinzia, Silani Vincenzo, Kirby Janine, Pall Hardev, Morrison Karen E, Al-Chalabi Ammar, Weale Michael E, Brown Robert H, Landers John, Andersen Peter M, Baas Frank, Vianney de Jong J M B, de Belleroche Jacqueline, Morris Alex, Asbroek Anneloor Alm Ten, Schelhaas Helenius J, Scott Kirsten M, Troakes Claire, Lee Younbok, Miller Jack, Johnson Lauren, Topp Simon, Vance Caroline, Shatunov Aleksey, Newhouse Stephen, Jones Ashley, Gray Ian, Wright Jamie, Nestor Peter J, Weber Markus, Sapp Peter C, Lovestone Simon, Lupton Michelle, Powell John, Rogelj Boris, Al-Sarraj Safa, Hortobágyi Tibor, Smith Bradley N

Zitation

Shaw C, Shaw P, Robberecht W, Van Damme P, Veldink J, Van den Berg L, Ticozzi N, Taroni F, Gellera C, Silani V, Kirby J, Pall H, Morrison K, Al-Chalabi A, Weale M, Brown R, Landers J, Andersen P, Baas F, Vianney de Jong J, de Belleroche J, Morris A, Asbroek A, Schelhaas H, Scott K, Troakes C, Lee Y, Miller J, Johnson L, Topp S, Vance C, Shatunov A, Newhouse S, Jones A, Gray I, Wright J, Nestor P, Weber M, Sapp P, Lovestone S, Lupton M, Powell J, Rogelj B, Al-Sarraj S, Hortobágyi T, Smith B. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. Eur J Hum Genet 2012; 21:102-8.

Art

Wissenschaftlicher Artikel/Review (Englisch)

Zeitschrift

Eur J Hum Genet 2012; 21

Veröffentlichungsdatum

13.06.2012

eISSN (Online)

1476-5438

Seiten

102-8

Kurzbeschreibung/Zielsetzung

A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.