A Specific Diplotype H1j/H2 of the MAPT Gene Could Be Responsible for Parkinson’s Disease with Dementia

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease. Five to ten percent of patients have monogenic form of the disease, while most of sporadic PD cases are caused by the combination of genetic and environmental factors. Microtubule-associated protein tau (MAPT) has been appointed as one of the most important risk factors for several neurodegenerative diseases including PD. MAPT is characterized by an inversion in chromosome 17 resulting in two distinct haplotypes H1 and H2. Studies described a significant association of MAPT H1j subhaplotype with PD risk, while H2 haplotype was associated with Parkinsonism, particularly to its bradykinetic component. We report here an isolated case displaying an akinetic-rigid form of PD, with age of onset of 41 years and a good response to levodopa, who developed dementia gradually during the seven years of disease progression. The patient does not carry the LRRK2 G2019S mutation, copy number variations, nor pathogenic and rare variants in known genes associated with PD. MAPT subhaplotype genotyping revealed that the patient has the H1j/H2 diplotype, his mother H1j/H1j, his two healthy brothers H1j/H1v and his deceased father was by deduction H1v/H2. The H1j/H2 diplotype was shown in a total of 3 PD patients among 80, who also did not have known PD-causing mutation and in 1 out of 92 healthy individual controls. The three patients with this diplotype all have a similar clinical phenotype. Our results suggest that haplotypes H1j and H2 are strong risk factor alleles, and their combination could be responsible for early onset of PD with dementia.

Gene Set-Based Analysis of the Endosomal Sorting Processes Cargo Selection and Membrane Tubulation with Human Reward System Reactivity

“…The second gene, DNAJC13, which is the only gene implicated across both of our samples, is of particular importance for coordination between retromer and WASH, because DNAJC13 regulates the packaging process spatially and temporally, by ensuring that the requisite elements of the transport machinery are present at the microdomain (Freeman et al, 2014;Fujibayashi et al, 2008;Girard, Poupon, Blondeau, & McPherson, 2005). rs3762672 mediates an amino-acid change of the hydrophobic residue alanine to the polar residue serine at amino acid position 1463 in the human protein, and has been observed in Parkinson's disease with dementia in a single case, however with unclear relevance (Smaili et al, 2020). The involvement of DNAJC13 in dopaminergic neurotransmission in the present study may provide a mechanistic explanation of previous reports for DNAJC13, where rare missense variants of this gene contributed to Parkinson´s disease (https://www.omim.org/entry/616361) (Yoshida et al, 2018), and gene expression and rare disruptive mutations were implicated in schizophrenia (Piras et al, 2019;Wu, Yao, & Luo, 2017).…”