GRN – GRN-related Frontotemporal Lobar Degeneration with TDP-43 Inclusions

Frontotemporal lobar degeneration with ubiquitin-positive, TDP-43 inclusions (FTLD-TDP) is predominantly caused by heterozygous loss-of-function mutations in the progranulin gene (GRN), leading to progranulin haploinsufficiency and adult-onset behavioral and language dysfunction. The inheritance mode is autosomal dominant, with complete penetrance by the sixth decade in many families. Clinical diagnosis is supported by neuroimaging showing predominant frontal and temporal atrophy, and neuropathology reveals tau-negative, ubiquitin-positive inclusions rich in TDP-43.

Genetic evidence for GRN in FTLD-TDP is definitive. Null mutations were first identified in a Belgian founder family, including a splice donor mutation IVS0+5G>C and initiation codon variants resulting in mRNA degradation and truncated proteins, with segregation in multiple affected relatives ([PMID:16862115]). In a cohort of 378 FTLD patients, PGRN mutations were present in 10% (n = 38 probands)[PMID:16950801] and in 23% of familial cases, confirming a recurrent founder effect. Additional familial series identified R493X in two probands and their affected relatives, further validating segregation across at least 19 family members.

The variant spectrum encompasses over 23 distinct pathogenic alleles, including nonsense, frameshift, splice-site, and signal peptide mutations. Recurrent mutations include c.373C>T (p.Gln125Ter), c.1477C>T (p.Arg493Ter), and c.1166_1167del (p.Cys389fs), which lead to premature stop codons and triggers of nonsense-mediated decay. Missense variants in the signal peptide (e.g., c.26C>A [p.Ala9Asp]) and core granulin domains also result in impaired secretion or stability. Non-coding variation at rs5848 (c.*78C>T) modulates miR-659 binding and reduces progranulin levels, mimicking haploinsufficiency in homozygous carriers ([PMID:18723524]).

Functional studies demonstrate that PGRN haploinsufficiency is the primary mechanism. Cellular assays show that null and signal-sequence mutations reduce GRN mRNA and secreted protein levels, with missorting and impaired cleavage in the secretory pathway. Grn knockout mice exhibit reduced survival, gliosis, ubiquitin-positive accumulations, and elevated hyperphosphorylated TDP-43 in detergent-insoluble brain fractions, recapitulating human FTLD-TDP neuropathology ([PMID:22733568]). Rescue experiments in zebrafish confirm PGRN’s neurotrophic role, where human progranulin corrects axonopathy induced by PGRN knockdown or mutant TDP-43.

Some studies have investigated GRN variation in other neurodegenerative diseases. No association was found between rs5848 and Parkinson’s disease risk in two Caucasian series (n = 1 413)[PMID:19473366], nor is there a major role for GRN mutations in Alzheimer’s disease cohorts without FTLD pathology. These data support disease specificity of GRN haploinsufficiency for FTLD-TDP.

In summary, heterozygous GRN loss-of-function mutations cause autosomal dominant FTLD-TDP through progranulin haploinsufficiency. Genetic testing for GRN null and pathogenic missense variants informs diagnosis and family counseling. Functional concordance across cellular and animal models underscores the therapeutic potential of restoring progranulin levels.

Key Take-home: GRN haploinsufficiency is a definitive cause of FTLD-TDP, and genetic screening for PGRN null alleles is critical for clinical management.

References

• Nature • 2006 • Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 PMID:16862115
• Human molecular genetics • 2006 • Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration PMID:16950801
• European journal of neurology • 2009 • GRN 3'UTR+78 C>T is not associated with risk for Parkinson's disease. PMID:19473366
• Journal of pathology • 2012 • Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice. PMID:22733568
• Human molecular genetics • 2008 • Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. PMID:18723524

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