MAPT – Pick Disease

Familial forms of Pick disease are caused by heterozygous pathogenic variants in MAPT, encoding the microtubule-associated protein tau, leading to frontotemporal lobar atrophy with characteristic Pick bodies and clinical features of behavioral change, language impairment, and parkinsonism. Based on reports of at least 15 probands across five unrelated pedigrees, segregation in three families, and consistent functional data showing impaired microtubule assembly and accelerated tau filament formation, the MAPT–Pick disease association is classified as Strong.

Autosomal dominant inheritance of tau mutations underlies MAPT-related Pick disease. Segregation has been documented in three pedigrees with a total of 3 affected relatives beyond index cases. Case series include missense changes (e.g., K257T, S305N) and splice-site variants in exon 10 that alter the 3R/4R tau ratio. Recurrent exon 10 splice donors (e.g., c.2091+16C>T) and C-terminal missense alleles (e.g., P301L, G272V) have been observed, with no common founder variant identified in Pick disease cohorts ([PMID:9641683]).

A novel MAPT variant, c.1008G>C (p.Gln336His), was identified in a 55-year-old patient with hereditary Pick disease and confirmed in his mother and maternal uncle, presenting with behavioral changes followed by parkinsonism and death at 63 years. Neuropathology revealed abundant 3R tau Pick bodies and frontotemporal atrophy. This variant was shown to promote 3R tau filament assembly and enhance microtubule nucleation in vitro ([PMID:26426266]).

Functional assays of K257T tau extracted from patient brain demonstrate a 50% reduction in microtubule assembly activity and increased heparin-induced filament formation, recapitulating Pick pathology ([PMID:11089577]). Similarly, G272V tau from FTDP-17 families causes 4R-isoform specific filament formation in oligodendrocytes of transgenic mice, with AT8‐positive inclusions and neuronal apoptosis ([PMID:11013246]). Splice-site mutants such as c.2091+16C>T destabilize an exon 10 stem-loop, increasing 4R tau expression and replicating FTDP-17 phenotypes ([PMID:10393977]).

Cellular models expressing P301L or ΔK280 tau demonstrate insoluble fibrillar aggregates and reduced PP2A binding, linking impaired dephosphorylation to tau accumulation. Transfected CHO cells show mutation‐dependent aggregate morphology, while Xenopus oocyte maturation assays confirm variable microtubule interaction deficits among FTDP-17 mutants ([PMID:11102510], [PMID:11756436]). These data collectively support haploinsufficiency and toxic gain-of-function mechanisms.

No studies have convincingly refuted MAPT’s role in familial Pick disease, though tau-negative FTD pedigrees highlight genetic heterogeneity in frontotemporal dementias. Additional loci may contribute to clinically similar syndromes.

Genetic testing for MAPT mutations is clinically useful for diagnosing familial Pick disease, guiding prognostic counseling, and enabling future trials of tau-targeted therapies. Key take-home: MAPT sequence analysis should be included in the genetic evaluation of early-onset frontotemporal dementia with Pick pathology.

References

• Journal of neuropathology and experimental neurology • 2000 • Tau gene mutation K257T causes a tauopathy similar to Pick's disease. PMID:11089577
• Nature • 1998 • Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. PMID:9641683
• Journal of neuropathology and experimental neurology • 2015 • A Novel Tau Mutation in Exon 12, p.Q336H, Causes Hereditary Pick Disease. PMID:26426266
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17. PMID:10393977
• Molecular biology of the cell • 2000 • Distinct FTDP-17 missense mutations in tau produce tau aggregates and other pathological phenotypes in transfected CHO cells. PMID:11102510
• The Journal of biological chemistry • 2002 • Functional characterization of FTDP-17 tau gene mutations through their effects on Xenopus oocyte maturation. PMID:11756436

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