A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study

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• 作者：Ilse Gijselinck PhD^a ;   ; ^b ; Tim Van Langenhove MD^a ;   ; ^b ;   ; ^c ; Julie van der Zee PhD^a ;   ; ^b ; Kristel Sleegers PhD^a ;   ; ^b ; Sté ; phanie Philtjens MSc^a ;   ; ^b ; Gernot Kleinberger MSc^a ;   ; ^b ; Jonathan Janssens MSc^a ;   ; ^b ; Karolien Bettens PhD^a ;   ; ^b ; Caroline Van Cauwenberghe MSc^a ;   ; ^b ; Sandra Pereson MSc^a ;   ; ^b ; Sebastiaan Engelborghs ProfPhD^b ;   ; ^d ; Anne Sieben MD^a ;   ; ^b ;   ; ^e ; Peter De Jonghe ProfPhD^a ;   ; ^b ;   ; ^c ; Rik Vandenberghe ProfPhD^f ; Patrick Santens ProfPhD^e ; Jan De Bleecker ProfPhD^e ; Githa Maes MSc^a ;   ; ^b ; Veerle B&#228 ; umer BSc^a ;   ; ^b ; Lubina Dillen PhD^a ;   ; ^b ; Geert Joris BSc^a ;   ; ^b ; Ivy Cuijt MSc^a ;   ; ^b ; Ellen Corsmit BSc^a ;   ; ^b ; Ellen Elinck MSc^a ;   ; ^b ; Jasper Van Dongen BSc^a ;   ; ^b ; Steven Vermeulen MSc^a ;   ; ^b ; Marleen Van den Broeck BSc^a ;   ; ^b ; Carolien Vaerenberg MSc^a ;   ; ^b ; Maria Mattheijssens BSc^a ;   ; ^b ; Karin Peeters BSc^a ;   ; ^b ; Wim Robberecht ProfPhD^f ;   ; ^g ; Patrick Cras ProfPhD^b ;   ; ^c ; Jean-Jacques Martin ProfPhD^b ; Peter P De Deyn ProfPhD^b ;   ; ^d ; Marc Cruts ProfPhD^a ;   ; ^b ; Christine Van Broeckhoven ProfDSc^a ;   ; ^b ;   ; ^{christine.vanbroeckhoven@molgen.vib-ua.be}
• 刊名：Lancet Neurology
• 出版年：2012
• 出版时间：January 2012
• 年：2012
• 卷：11
• 期：1
• 页码：54-65
• 全文大小：935 K

文摘

Summary

Background

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are extremes of a clinically, pathologically, and genetically overlapping disease spectrum. A locus on chromosome 9p21 has been associated with both disorders, and we aimed to identify the causal gene within this region.

Methods

We studied 305 patients with FTLD, 137 with ALS, and 23 with concomitant FTLD and ALS (FTLD-ALS) and 856 controls from Flanders (Belgium); patients were identified from a hospital-based cohort and were negative for mutations in known FTLD and ALS genes. We also examined the family of one patient with FTLD-ALS previously linked to 9p21 (family DR14). We analysed 130 kbp at 9p21 in association and segregation studies, genomic sequencing, repeat genotyping, and expression studies to identify the causal mutation. We compared genotype-phenotype correlations between mutation carriers and non-carriers.

Findings

In the patient-control cohort, the single-nucleotide polymorphism rs28140707 within the 130 kbp region of 9p21 was associated with disease (odds ratio [OR] 2¡¤6, 95 % CI 1¡¤5?¡¤7; p=0¡¤001). A GGGGCC repeat expansion in C9orf72 completely co-segregated with disease in family DR14. The association of rs28140707 with disease in the patient-control cohort was abolished when we excluded GGGGCC repeat expansion carriers. In patients with familial disease, six (86 % ) of seven with FTLD-ALS, seven (47 % ) of 15 with ALS, and 12 (16 % ) of 75 with FTLD had the repeat expansion. In patients without known familial disease, one (6 % ) of 16 with FTLD-ALS, six (5 % ) of 122 with ALS, and nine (4 % ) of 230 with FTLD had the repeat expansion. Mutation carriers primarily presented with classic ALS (10 of 11 individuals) or behavioural variant FTLD (14 of 15 individuals). Mean age at onset of FTLD was 55¡¤3 years (SD 8¡¤4) in 21 mutation carriers and 63¡¤2 years (9¡¤6) in 284 non-carriers (p=0¡¤001); mean age at onset of ALS was 54¡¤5 years (9¡¤9) in 13 carriers and 60¡¤4 years (11¡¤4) in 124 non-carriers. Postmortem neuropathological analysis of the brains of three mutation carriers with FTLD showed a notably low TDP-43 load. In brain at postmortem, C9orf72 expression was reduced by nearly 50 % in two carriers compared with nine controls (p=0¡¤034). In familial patients, 14 % of FTLD-ALS, 50 % of ALS, and 62 % of FTLD was not accounted for by known disease genes.

Interpretation

We identified a pathogenic GGGGCC repeat expansion in C9orf72 on chromosome 9p21, as recently also reported in two other studies. The GGGGCC repeat expansion is highly penetrant, explaining all of the contribution of chromosome 9p21 to FTLD and ALS in the Flanders-Belgian cohort. Decreased expression of C9orf72 in brain suggests haploinsufficiency as an underlying disease mechanism. Unidentified genes probably also contribute to the FTLD-ALS disease spectrum.

Funding

Full funding sources listed at end of paper (see Acknowledgments).