Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Neuronal ceroid lipofuscinosis (NCL) is a group of rare lysosomal storage disorders.
• Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a common early-onset dementia.
• Heterozygous mutations in the progranulin gene (GRN) are a primary cause of FTLD-TDP.

Purpose of the Study:

• To identify the genetic cause of NCL in a family with two affected siblings.
• To investigate the phenotypic spectrum of progranulin gene mutations.

Main Methods:

• Hypothesis-free linkage analysis and exome sequencing were performed.
• Genetic analysis identified homozygous mutations in the GRN gene.
• Progranulin-deficient mouse models were re-examined.

Main Results:

• Two siblings with NCL were found to be homozygous for a novel c.813_816del mutation in GRN.
• This mutation was located within a linkage peak on chromosome 17.
• Progranulin-deficient mice exhibited neuropathological features consistent with NCL.

Conclusions:

• Homozygous GRN mutations can cause NCL, a distinct neurological disorder from FTLD-TDP.
• This study reveals an unexpected link between NCL and FTLD-TDP.
• GRN mutations exhibit pleiotropic effects depending on heterozygous or homozygous states.