Identification of 2 Loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
BACKGROUND
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative brain disorder that can be accompanied by signs of amyotrophic lateral sclerosis (ALS).


OBJECTIVE
To identify a novel gene for FTLD-ALS.


METHODS
Genome-wide linkage study in a multiplex family with FTLD-ALS with subsequent fine mapping and mutation analyses.


METHODS
Memory Clinic of the Middelheim General Hospital.


METHODS
An extended Belgian family with autosomal dominant FTLD-ALS, DR14, with a mean age at onset of 58.1 years (range, 51-65 years [n = 9]) and mean disease duration of 6.4 years (range, 1-17 years [n = 9]). The proband with clinical FTLD showed typical FTLD pathology with neuronal ubiquitin-immunoreactive inclusions that were positive for the transactivation response DNA-binding protein 43 (TDP-43).


METHODS
Linkage to chromosome 9 and 14.


RESULTS
We found significant linkage to chromosome 9p23-q21 (multipoint logarithm of odds [LOD] score = 3.38) overlapping with a known FTLD-ALS locus (ALSFTD2) and nearly significant linkage to a second locus at chromosome 14q31-q32 (multipoint LOD score = 2.79). Obligate meiotic recombinants defined candidate regions of 74.7 megabase pairs (Mb) at chromosome 9 and 14.6 Mb near the telomere of chromosome 14q. In both loci, the disease haplotype segregated in all patients in the family. Mutation analysis of selected genes and copy number variation analysis in both loci did not reveal segregating pathogenic mutations.


CONCLUSIONS
Family DR14 provides additional significant evidence for the importance of the chromosome 9 gene to FTLD-ALS and reveals a possible novel locus for FTLD-ALS at chromosome 14. The identification of the underlying genetic defect(s) will significantly contribute to the understanding of neurodegenerative disease mechanisms in FTLD, ALS, and associated neurodegenerative disorders.
Gijselinck
Ilse
I
University of Antwerp, B-2610 Antwerp, Belgium.
Engelborghs
Sebastiaan
S
Maes
Githa
G
Cuijt
Ivy
I
Peeters
Karin
K
Mattheijssens
Maria
M
Joris
Geert
G
Cras
Patrick
P
Martin
Jean-Jacques
JJ
De Deyn
Peter P
PP
Kumar-Singh
Samir
S
Van Broeckhoven
Christine
C
Cruts
Marc
M
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001530:Belgium; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000473:pathology