A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia

Morita, Mitsuya; Al‐Chalabi, Ammar; Andersen, P. M.; Hosler, Betsy A.; Sapp, PC; Englund, Elisabet; Mitchell, John E.; Habgood, James; Belleroche, Jackie de; Xi, Jing; Jongjaroenprasert, Wallaya; Horvitz, H. Robert; Gunnarsson, Lars‐Gunnar; Brown, Robert H.

doi:10.1212/01.wnl.0000200048.53766.b4

Cited by 332 publications

(207 citation statements)

References 51 publications

(53 reference statements)

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“…In 2006, we reported linkage to a 11-Mb locus on chromosome 9p13.2-21.3 in Dutch and Scandanavian kindreds with autosomal-dominant ALS-FTD. 3,4 Linkage was subsequently confirmed in eight other dominant kindreds defining a minimal overlapping region of B3.6 Mb. 5,6 Genome-wide association studies in sporadic and familial ALS demonstrated highly significant association with single-nucleotide polymorphisms (SNPs) across a 170-Kb region at 9p21.2.…”

Section: Introductionmentioning

confidence: 88%

“…DNA from 12 individuals carrying the disease haplotype and 4 without from our previously linked kindred, 3 2 affected members from the previously published linked Scandanavian family, 4 14 cases with suggested linkage to ch9p and 21 other individuals with familial ALS þ / ÀFTD were processed for DNA capture using custom-designed overlapping probes (Roche Nimblegen, Madison, WI, USA) across the 3.6-Mb locus between D9S169 (27 238 617) 5 and D9S251 (30 819 382). 6 A total of 5 mg of DNA was fragmented with a Bioruptor (Wolf Laboratories Ltd, York, UK) at 30 s on/off bursts for 45 mins to sizes of 200-300 bp.…”

Section: P212 Locus-capture and Sequencingmentioning

confidence: 99%

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

et al. 2012

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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 þ / ÀFTD from five European cohorts (total n ¼ 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n ¼ 434) and controls (n ¼ 856). Haplotypes were analysed using PLINK and aged using DMLE þ . In a London clinic cohort, the HREM was the most common mutation in familial ALS þ / ÀFTD: 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 þ / ÀFTD 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, Po10 À8 ). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.

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Section: Introductionmentioning

confidence: 88%

Section: P212 Locus-capture and Sequencingmentioning

confidence: 99%

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

et al. 2012

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“…In addition, a locus on chromosome 9p21, for which the gene has not yet been identified, is responsible for a form of ALS with frontotemporal lobar degeneration (FTLD). [10][11][12] FTLD is a heterogeneous group of neurodegenerative disorders that have in common behavioral and/or language dysfunction and are now considered to be the most common non-motor deficit in ALS patients. [12][13][14] There is a growing body of evidence that a spectrum of frontal lobe dysfunction is present in up to 50% of ALS patients, with as many as 20% showing abnormalities meeting Neary criteria for clinical FTLD.…”

Section: Introductionmentioning

confidence: 99%

TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

Deerlin

Leverenz

Bekris

et al. 2008

The Lancet Neurology

631

444

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“…FTLD and ALS belong to a clinicopathological spectrum of overlapping central nervous system (CNS) disorders and might also have common genetic etiologies. Clinically, both phenotypes may occur in the same patient (FTLD-ALS) [Lomen-Hoerth et al, 2003;Ringholz et al, 2005] or in the same family [Hosler et al, 2000;Vance et al, 2006;Morita et al, 2006;Valdmanis et al, 2007]. Pathologically, the TAR DNA binding protein 43 (TDP-43) was found as a major constituent of polyubiquitinated neuronal inclusions [Neumann et al, 2006] in both FTLDU and ALS patients [Neumann et al, 2006;Arai et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

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Communicated by Mark H. PaalmanMutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), [1373][1374][1375][1376][1377][1378][1379][1380][1381][1382][1383][1384][1385][1386] 2008.

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A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia

Abstract: A locus on chromosome 9p21.3-p13.3 is linked to ALS-FTD.

Cited by 332 publications

References 51 publications

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

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

TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

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