eprintid: 1358290
rev_number: 36
eprint_status: archive
userid: 608
dir: disk0/01/35/82/90
datestamp: 2012-08-31 18:52:18
lastmod: 2021-12-06 00:38:54
status_changed: 2012-08-31 18:52:18
type: article
metadata_visibility: show
item_issues_count: 0
creators_name: Smith, KR
creators_name: Damiano, J
creators_name: Franceschetti, S
creators_name: Carpenter, S
creators_name: Canafoglia, L
creators_name: Morbin, M
creators_name: Rossi, G
creators_name: Pareyson, D
creators_name: Mole, SE
creators_name: Staropoli, JF
creators_name: Sims, KB
creators_name: Lewis, J
creators_name: Lin, WL
creators_name: Dickson, DW
creators_name: Dahl, HH
creators_name: Bahlo, M
creators_name: Berkovic, SF
title: Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.
ispublished: pub
divisions: UCL
divisions: B02
divisions: D13
divisions: G23
keywords: Animals, Chromosome Mapping, DNA Mutational Analysis, Dementia, Family Health, Female, Genetic Linkage, Heterozygote, Homozygote, Humans, Intercellular Signaling Peptides and Proteins, Lod Score, Male, Mice, Mutation, Pedigree, Phenotype
note: 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
abstract: 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.
date: 2012-06-08
official_url: http://dx.doi.org/10.1016/j.ajhg.2012.04.021
oa_status: green
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article, Research Support, Non-U.S. Gov't
verified: verified_manual
elements_source: PubMed
elements_id: 411809
doi: 10.1016/j.ajhg.2012.04.021
pii: S0002-9297(12)00254-6
lyricists_name: Mole, Sara
lyricists_id: SEMOL61
full_text_status: public
publication: The American Journal of Human Genetics
volume: 90
number: 6
pagerange: 1102 - 1107
event_location: United States
issn: 0002-9297
citation:        Smith, KR;    Damiano, J;    Franceschetti, S;    Carpenter, S;    Canafoglia, L;    Morbin, M;    Rossi, G;                                         ... Berkovic, SF; + view all <#>        Smith, KR;  Damiano, J;  Franceschetti, S;  Carpenter, S;  Canafoglia, L;  Morbin, M;  Rossi, G;  Pareyson, D;  Mole, SE;  Staropoli, JF;  Sims, KB;  Lewis, J;  Lin, WL;  Dickson, DW;  Dahl, HH;  Bahlo, M;  Berkovic, SF;   - view fewer <#>    (2012)    Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.                   The American Journal of Human Genetics , 90  (6)   1102 - 1107.    10.1016/j.ajhg.2012.04.021 <https://doi.org/10.1016/j.ajhg.2012.04.021>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1358290/1/1358290.pdf