Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation Dosage
Open accessAbstract
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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- Authors
- Smith, K. R., Damiano, J., Franceschetti, S., Carpenter, S., Canafoglia, L., Morbin, M., Rossi, G., Pareyson, D., Mole, S. E., Staropoli, J. F., Sims, K. B., Lewis, J., Lin, W.-L., Dickson, D. W., Dahl, H.-H., Bahlo, M., & Berkovic, S. F.
- Affiliations
- The University of Melbourne (AU)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Hospital de São João (PT)
- MRC Laboratory for Molecular Cell Biology (GB)
- Massachusetts General Hospital (US)
- University of Florida (US)
- Mayo Clinic (US)
- Corresponding author
- Bahlo, Melanie
- Berkovic, Samuel F.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 90
- Issue
- 6
- Pages
- 1102-1107
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3370276
- OpenAlex
- W2039756269
- Cited by
- 489
- References
- 2
- Citations by year
- 2026: 22 · 2025: 31 · 2024: 27 · 2023: 29 · 2022: 35 · 2021: 49 · 2020: 45 · 2019: 44 · 2018: 36 · 2017: 40 · 2016: 40 · 2015: 28 · 2014: 26 · 2013: 22 · 2012: 13
- FWCI
- 18.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- progranulin, GRN mutations, neuronal ceroid lipofuscinosis, FTLD-TDP, frontotemporal lobar degeneration, pleiotropy, homozygous mutation, heterozygous mutation, linkage analysis, familial neurodegenerative disease
- MeSH terms
- Progranulins, Animals, Chromosome Mapping, Dementia, DNA Mutational Analysis, Family Health, Female, Heterozygote, Homozygote, Humans, Genetic Linkage, Lod Score, Male, Mutation, Pedigree, Phenotype, Intercellular Signaling Peptides and Proteins, Mice
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