Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage |
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Authors: | Smith Katherine R Damiano John Franceschetti Silvana Carpenter Stirling Canafoglia Laura Morbin Michela Rossi Giacomina Pareyson Davide Mole Sara E Staropoli John F Sims Katherine B Lewis Jada Lin Wen-Lang Dickson Dennis W Dahl Hans-Henrik Bahlo Melanie Berkovic Samuel F |
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Institution: | Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. |
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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. |
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