Abstract
Loss-of-function GRN mutations lead to GRN haploinsufficiency and consequently neurodegeneration with significant heterogeneity in clinical presentation of various syndromes. The aim of this study was to investigate the genetics and clinical features of patients with GRN-related frontotemporal lobar degeneration (FTLD) syndromes. We performed mutation analysis of GRN in 45 unrelated Canadian patients with a broad spectrum of FTLD-like syndromes (mean age at onset of 64.0 ± 11.2 years). In our cohort, two patients were carriers of two novel heterozygous alterations in GRN: 2 bp insertion (c.769–770insCC:p.Q257fs) and 12 bp deletion (c.1009–1020del:p.337–340del). Both patients presented with corticobasal syndrome supported by clinical and radiological findings. The absence of the mutant allele in the RT–PCR product was only observed for the sample with 2 bp insertion in GRN. In contrast, the allele with 12 bp deletion in GRN was not down-regulated at the RNA level and did not segregate with FTLD in the family. Our report extends the evidence for genetic and phenotypic variability in FTLD disorders, and detects a novel pathogenic GRN mutation, carriers of which could eventually help to evaluate the efficacy of different treatments at early stages of dementia.
Highlights
Progranulin (GRN), encoded by the GRN gene on chromosome 17q21, is a multifunctional growth factor, which is expressed in the brain by microglia and neurons, and is critical in maintaining neuronal survival[1]
We identified two novel GRN mutations in two patients clinically diagnosed with corticobasal syndrome (CBS)
Clinical symptoms of case 10162 began with a gradual decline in her cognition including comprehension, memory, executive and visuospatial impairment. This progressed to apraxia and neglect on her left side, and parkinsonism
Summary
Progranulin (GRN), encoded by the GRN gene on chromosome 17q21, is a multifunctional growth factor, which is expressed in the brain by microglia and neurons, and is critical in maintaining neuronal survival[1]. Loss-of-function GRN mutations lead to GRN haploinsufficiency and neurodegeneration[2]. These mutations are associated with high phenotypic variability and have been identified in a number of neurodegenerative syndromes that fall under the umbrella term of frontotemporal lobar degeneration (FTLD), including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), and corticobasal syndrome (CBS)[3,4]. Cognitive dysfunction and progressive non-fluent aphasia tend to be more frequent in patients with CBS caused by GRN mutations. We describe the clinical, radiological, and genetic findings in a cohort of Canadian FTLD patients, including two with novel GRN mutations, which extend the knowledge on the phenotypic variability and mutation spectrum of GRN
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