Objective: To report the identification of a novel intronic variant in MAPT in a patient with familial parkinsonism-frontotemporal lobar degeneration (FTLD).

Background: MAPT mutations are a common cause of familial FTLD. Alternative splicing of exon 10 leads to isoforms containing either three or four (4R) microtubule binding repeats. 4R tau aggregates more readily and is found in greater ratio in FTD, CBD and PSP. Reported intronic mutations that favor retention of exon 10 are associated with increased levels of 4R tau and cause autosomal dominant FTLD with parkinsonism.

Method: Brain pathology analysis with immunostains for tau, p62, beta amyloid, alpha synuclein and phosphorylated TDP-43; whole-exome sequencing (WES) and tau protein studies from frontal cortex protein lysates were performed to study this case.

Results: A 45-year-old female presented with 15 months of progressive cognitive changes, gait slowing, trismus, dysphagia and dysarthria. Exam displayed frontal release signs, diffuse muscle atrophy, parkinsonism and upper motor neuron findings. Family pedigree was significant for two deceased siblings diagnosed with early-onset dementia. DaTScan showed decreased bilateral uptake. MRI Brain showed non-specific volume loss. Symptoms did not respond to baclofen, levodopa, amantadine or botox. Patient eventually transitioned to palliative care and passed away three years after disease onset. Primary brain pathology was consistent with an unclassifiable tauopathy with co-localization of tufted astrocytes and astrocytic plaques in the striatum, temporal, parietal, and motor cortices. WES showed a variant in MAPT in intron 9 +13 A > C, which was confirmed by Sanger sequencing. The variant is absent in gnomAD. Western blot with lysate and sarkosyl-insoluble fractions from frontal cortex showed that insoluble pathological tau was exclusively 4R-tau and soluble tau had an excess of 4R-tau.

Conclusion: We present a patient with FTLD with parkinsonism carrying a novel intronic variant in MAPT. This variant causes increased production of 4R-tau, leading to insoluble inclusions, composed exclusively of 4R-tau, indicating an increased inclusion of exon 10. Our findings broaden the genetic spectrum of MAPT intronic variants associated with 4R-tau overproduction, suggesting that critical regulatory elements controlling exon 10 splicing are also located in the 5’ region of intron 9.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-intronic-variant-in-mapt-causes-ftld-parkinsonism-implications-for-regulatory-mechanism-of-mapt-pre-mrna-splicing/