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Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation Dosage


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
2012-06-08
AMERICAN JOURNAL OF HUMAN GENETICS
Journal Article
90
6
1102-1107
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.
CELL PRESS
FRONTOTEMPORAL LOBAR DEGENERATION; NEURONAL CEROID-LIPOFUSCINOSIS; INBREEDING COEFFICIENT; SEQUENCING DATA; KUFS-DISEASE; GENE; HOMOZYGOSITY; VARIABILITY; DISORDERS; DEMENTIA
Bioinformatics
10.1016/j.ajhg.2012.04.021
Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.