TY  - JOUR
ID  - discovery1358290
N2  - We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs?10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.
KW  - Animals
KW  -  Chromosome Mapping
KW  -  DNA Mutational Analysis
KW  -  Dementia
KW  -  Family Health
KW  -  Female
KW  -  Genetic Linkage
KW  -  Heterozygote
KW  -  Homozygote
KW  -  Humans
KW  -  Intercellular Signaling Peptides and Proteins
KW  -  Lod Score
KW  -  Male
KW  -  Mice
KW  -  Mutation
KW  -  Pedigree
KW  -  Phenotype
TI  - Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.
EP  -  1107
AV  - public
Y1  - 2012/06/08/
SN  - 0002-9297
UR  - http://dx.doi.org/10.1016/j.ajhg.2012.04.021
JF  - The American Journal of Human Genetics
A1  - Smith, KR
A1  - Damiano, J
A1  - Franceschetti, S
A1  - Carpenter, S
A1  - Canafoglia, L
A1  - Morbin, M
A1  - Rossi, G
A1  - Pareyson, D
A1  - Mole, SE
A1  - Staropoli, JF
A1  - Sims, KB
A1  - Lewis, J
A1  - Lin, WL
A1  - Dickson, DW
A1  - Dahl, HH
A1  - Bahlo, M
A1  - Berkovic, SF
SP  - 1102 
VL  - 90
N1  - This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PMCID: PMC3370276
IS  - 6
ER  -