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Frontotemporal dementia (FTD) is a presenile neurodegenerative disorder characterized by progressive behavioral and executive dysfunction. Rare autosomal dominant mutations in CHMP2B, a core subunit of the endosomal ESCRT-III complex, underlie FTD linked to chromosome 3 (FTD3) (PMID:16041373). In the original Danish pedigree, the c.532-1G>C splice-acceptor variant causes aberrant exon 6 retention and C-terminal truncation of CHMP2B (PMID:16041373). A second branch of this family and unrelated Belgian patients harbor the same splice defect (PMID:18484988). Novel heterozygous splice-site variants (c.532-2A>T, c.35-1G>A) and C-terminal truncating mutations have been described in Chinese and Spanish patients, expanding the mutational spectrum (PMID:37272767; PMID:40244880). Age at onset is typically in the fifth to sixth decade, with prominent personality changes and behavioral disinhibition.
Inheritance is autosomal dominant with segregation of pathogenic CHMP2B variants in at least 19 affected relatives across four families (PMID:16041373; PMID:18484988). At least five unrelated probands have been reported carrying splice-site or truncating alleles. No alternative genetic etiology was identified in mutation carriers, and large screenings in sporadic cohorts failed to detect pathogenic CHMP2B variants (PMID:20625756). The consistent AD inheritance and co-segregation strongly support a disease-causing role for these variants.
Pathogenic alleles are dominated by splice-site mutations affecting exon 6 (c.532-1G>C, c.532-2A>T) or exon 1 (c.35-1G>A) that result in C-terminal truncations (e.g., p.Gln165Ter, p.Met178ValfsTer2). A single rare missense change, c.442G>T (p.Asp148Tyr), has been observed but lacks clear segregation and may represent a variant of uncertain significance. Loss-of-function alleles are absent from population databases, whereas common missense polymorphisms do not associate with FTD. There is no evidence for recurrent founder variants outside the Danish pedigree.
Functional studies demonstrate that C-terminally truncated CHMP2B proteins disrupt endosome–lysosome fusion and autophagic flux. Patient fibroblasts and brain tissue exhibit enlarged endosomal structures and impaired Rab7-dependent fusion with lysosomes (PMID:20223751). RNA interference targeting CHMP2B in patient cells reverses endosomal pathology, confirming direct causality (PMID:22786763). Transgenic mice expressing mutant CHMP2B develop p62- and ubiquitin-positive neuronal inclusions and progressive neurodegeneration, consistent with a toxic gain-of-function mechanism. Drosophila models further implicate the Toll pathway in modulating CHMP2B toxicity.
Screening studies in French and Finnish FTLD cohorts found no additional pathogenic CHMP2B alleles, underscoring the rarity of CHMP2B-mediated FTD (PMID:20625756; PMID:20412296). Common CHMP2B SNPs are not associated with sporadic FTD (PMID:16979267). Missense variants such as p.Ser187Asn and p.Ile29Val detected in controls require cautious interpretation and are not currently classified as pathogenic.
In summary, splice-site and truncating CHMP2B variants cause autosomal dominant FTD by perturbing ESCRT-III function, leading to endolysosomal dysfunction and neurodegeneration. CHMP2B genetic testing is clinically indicated in early-onset familial FTD with predominant behavioral features. Genetic counseling should address the low allele frequency and high penetrance of truncating variants. Therapeutic strategies targeting endolysosomal pathways, such as ESCRT modulation, warrant further exploration. Key Take-home: CHMP2B C-terminal truncations represent a rare but well-validated cause of autosomal dominant FTD with strong segregation and concordant functional evidence.
Gene–Disease AssociationModerateAutosomal dominant inheritance with segregation in 19 affected relatives across four families and five independent probands (PMID:16041373; PMID:18484988). Genetic EvidenceModerateFour splice-site or truncating LoF variants in four kindreds, with segregation in 19 relatives and no pathogenic alleles in large sporadic cohorts. Functional EvidenceModerateIn vitro and in vivo models demonstrate ESCRT-III dysfunction, endosomal pathology and rescue by RNAi (PMID:20223751; PMID:22786763). |