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

Research output: Contribution to journalArticlepeer-review


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.Thr272Serfs10) 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.

Original languageEnglish
Pages (from-to)1102-1107
Number of pages6
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - Jun 8 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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