2. Academic Validation
  3. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage

Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage

  • Am J Hum Genet. 2012 Jun 8;90(6):1102-7. doi: 10.1016/j.ajhg.2012.04.021.
Katherine R Smith 1,  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
Affiliations

Affiliation

  • 1 Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
PMID: 22608501 DOI: 10.1016/j.ajhg.2012.04.021
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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