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 journalArticle

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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.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 (US)
Pages (from-to)1102-1107
Number of pages6
JournalAmerican Journal of Human Genetics
Volume90
Issue number6
DOIs
StatePublished - Jun 8 2012

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Neuronal Ceroid-Lipofuscinoses
Frontotemporal Lobar Degeneration
Phenotype
Mutation
Exome
Chromosomes, Human, Pair 17
Chromosomes, Human, Pair 7
Nervous System Diseases
Age of Onset
Dementia
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Smith, K. R., Damiano, J., Franceschetti, S., Carpenter, S., Canafoglia, L., Morbin, M., ... Berkovic, S. F. (2012). Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. American Journal of Human Genetics, 90(6), 1102-1107. https://doi.org/10.1016/j.ajhg.2012.04.021

Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. / 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.

In: American Journal of Human Genetics, Vol. 90, No. 6, 08.06.2012, p. 1102-1107.

Research output: Contribution to journalArticle

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, WL, Dickson, DW, Dahl, HH, Bahlo, M & Berkovic, SF 2012, 'Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage', American Journal of Human Genetics, vol. 90, no. 6, pp. 1102-1107. https://doi.org/10.1016/j.ajhg.2012.04.021
Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M et al. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. American Journal of Human Genetics. 2012 Jun 8;90(6):1102-1107. https://doi.org/10.1016/j.ajhg.2012.04.021
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. / Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 6. pp. 1102-1107.
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