Medicine (Austin & Northern Health) - Research Publications

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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, W-L ; Dickson, DW ; Dahl, H-H ; Bahlo, M ; Berkovic, SF (CELL PRESS, 2012-06-08)

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.