Journal article

Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation Dosage

Katherine R Smith, John Damiano, Silvana Franceschetti, Stirling Carpenter, Laura Canafoglia, Michela Morbin, Giacomina Rossi, Davide Pareyson, Sara E Mole, John F Staropoli, Katherine B Sims, Jada Lewis, Wen-Lang Lin, Dennis W Dickson, Hans-Henrik Dahl, Melanie Bahlo, Samuel F Berkovic



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 ..

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Funding Acknowledgements

K.R.S. is supported by a PhD scholarship funded by the Pratt Foundation. S.F.B. is supported by a National Health and Medical Research Council (NHMRC) Australia Fellowship and an NHMRC Program Grant. M.B. is supported by an Australian Research Council (ARC) Future Fellowship and an NHMRC Program Grant. S.E.M. is supported by the Medical Research Council. The Batten Disease Support and Research Association supported S.E.M., J.S., and K.S. We thank Pawan Mann and Olivia Galante for technical assistance; Danya years, Robyn Ferguson, and Karen Oliver for technical support; the Rare NCL Gene Consortium for encouraging collaborative research on variant NCL cases; and the families and physicians for providing samples.