title: Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.
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.
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Smith
authors.forename: John
authors.initials: J
authors.lastname: Damiano
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.forename: Stirling
authors.initials: S
authors.lastname: Carpenter
authors.forename: Laura
authors.initials: L
authors.lastname: Canafoglia
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Giacomina
authors.initials: G
authors.lastname: Rossi
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mole
authors.forename: John F
authors.initials: JF
authors.lastname: Staropoli
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Sims
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Dahl
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008126:Lod Score; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D000077153:Progranulins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins