Smith, KR;
Damiano, J;
Franceschetti, S;
Carpenter, S;
Canafoglia, L;
Morbin, M;
Rossi, G;
... Berkovic, SF; + view all
(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.
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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.
| Type: | Article |
|---|---|
| Title: | Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ajhg.2012.04.021 |
| Publisher version: | http://dx.doi.org/10.1016/j.ajhg.2012.04.021 |
| Language: | English |
| Additional information: | 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 |
| 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 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1358290 |
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