Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation Dosage
- Author(s)
- 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;
- Details
- Publication Year 2012-06-08,Volume 90,Issue #6,Page 1102-1107
- Journal Title
- AMERICAN JOURNAL OF HUMAN GENETICS
- Publication Type
- Journal Article
- 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(star)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.
- Publisher
- CELL PRESS
- Keywords
- FRONTOTEMPORAL LOBAR DEGENERATION; NEURONAL CEROID-LIPOFUSCINOSIS; INBREEDING COEFFICIENT; SEQUENCING DATA; KUFS-DISEASE; GENE; HOMOZYGOSITY; VARIABILITY; DISORDERS; DEMENTIA
- Research Division(s)
- Bioinformatics
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370276/
- Publisher's Version
- https://doi.org/10.1016/j.ajhg.2012.04.021
- Terms of Use/Rights Notice
- Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.
Creation Date: 2012-06-08 12:00:00