Navigating the ALS Genetic Labyrinth: The Role of MAPT Haplotypes

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by wide clinical and biological heterogeneity, with a large proportion of ALS patients also exhibiting frontotemporal dementia (FTD) spectrum symptoms. This project aimed to characterize risk subtypes of the H1 haplotype within the MAPT (microtubule-associated protein tau) gene, according to their possible effect as a risk factor and as a modifying factor in relation to the age of disease onset. One hundred patients from Bulgaria with sporadic ALS were genotyped for the variants rs1467967, rs242557, rs1800547, rs3785883, rs2471738, and rs7521. Haploview 4.2 and SHEsisPlus were used to reconstruct haplotype frequencies using genotyping data from the 1000 Genomes project as controls. Genotype–phenotype correlation was investigated in the context of age of disease onset and risk of disease development. While the individual variants of the subtypes do not influence the age of onset of the disease, a correlation was found between the specific haplotype GGAGCA (H1b) and the risk of developing sALS, with results showing that individuals harboring this haplotype have a nearly two-fold increased risk of developing sALS compared to other H1 subtypes. The results from this study suggest that fine transcriptional regulation at the MAPT locus can influence the risk of ALS.

[1]  S. Tripathy,et al.  Shared genetic risk loci between Alzheimer’s disease and related dementias, Parkinson’s disease, and amyotrophic lateral sclerosis , 2023, Alzheimer's Research & Therapy.

[2]  T. Arzberger,et al.  Different MAPT haplotypes influence expression of total MAPT in postmortem brain tissue , 2023, Acta Neuropathologica Communications.

[3]  M. Valenti,et al.  Tau Isoforms: Gaining Insight into MAPT Alternative Splicing , 2022, International journal of molecular sciences.

[4]  Xiaohai Sun,et al.  Mutation spectrum of chinese amyotrophic lateral sclerosis patients with frontotemporal dementia , 2022, Orphanet Journal of Rare Diseases.

[5]  P. Reddy,et al.  Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies , 2022, International journal of molecular sciences.

[6]  A. Mukherjee,et al.  Recent Updates on the Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia , 2022, Molecular Neurobiology.

[7]  Ryan L. Collins,et al.  A genome-wide mutational constraint map quantified from variation in 76,156 human genomes , 2022, bioRxiv.

[8]  Jose A. Santiago,et al.  Key Disease Mechanisms Linked to Amyotrophic Lateral Sclerosis in Spinal Cord Motor Neurons , 2022, Frontiers in Molecular Neuroscience.

[9]  Derek H. Oakley,et al.  Novel genetic variants in MAPT and alterations in tau phosphorylation in amyotrophic lateral sclerosis post‐mortem motor cortex and cerebrospinal fluid , 2021, Brain pathology.

[10]  Xusheng Huang,et al.  Characteristics of Late-Onset Amyotrophic Lateral Sclerosis in a Chinese Cohort , 2021, Neurodegenerative Diseases.

[11]  R. Spataro,et al.  Tau protein as a diagnostic and prognostic biomarker in amyotrophic lateral sclerosis , 2021, European journal of neurology.

[12]  J. Quinn,et al.  Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the APOE and MAPT Haplotypes , 2021, Genes.

[13]  M. Goedert,et al.  Cryo-EM structures of tau filaments. , 2020, Current opinion in structural biology.

[14]  R. Hanajima,et al.  Cognitive and behavioral status in Japanese ALS patients: a multicenter study , 2020, Journal of Neurology.

[15]  Kevin L. Boehme,et al.  17q21.31 Sub-Haplotypes Underlying H1-Associated Risk for Parkinson's Disease and Progressive Supranuclear Palsy Converge on Altered Glial Regulation , 2020, SSRN Electronic Journal.

[16]  A. Ruiz,et al.  The MAPT H1 Haplotype Is a Risk Factor for Alzheimer’s Disease in APOE ε4 Non-carriers , 2019, Front. Aging Neurosci..

[17]  D. Fardo,et al.  Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy , 2019, Laboratory Investigation.

[18]  P. Hof,et al.  Association of MAPT haplotype‐tagging polymorphisms with cerebrospinal fluid biomarkers of Alzheimer's disease: A preliminary study in a Croatian cohort , 2018, Brain and behavior.

[19]  O. Andreassen,et al.  Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum , 2018, JAMA neurology.

[20]  O. Hardiman,et al.  Determining the incidence of familiality in ALS , 2018, Neurology: Genetics.

[21]  M. Strong,et al.  Phosphorylation of Threonine 175 Tau in the Induction of Tau Pathology in Amyotrophic Lateral Sclerosis—Frontotemporal Spectrum Disorder (ALS-FTSD). A Review , 2018, Front. Neurosci..

[22]  I. Deary,et al.  Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function , 2017, bioRxiv.

[23]  L. Buée,et al.  Tau deletion promotes brain insulin resistance , 2017, The Journal of experimental medicine.

[24]  L. Tan,et al.  Meta-analysis of the association between variants in MAPT and neurodegenerative diseases , 2017, Oncotarget.

[25]  Khleifat,et al.  What causes amyotrophic lateral sclerosis? , 2017, F1000Research.

[26]  Cedric E. Ginestet,et al.  Regional expression of the MAPT gene is associated with loss of hubs in brain networks and cognitive impairment in Parkinson disease and progressive supranuclear palsy , 2016, Neurobiology of Aging.

[27]  E. Rimm,et al.  A genome‐wide investigation of food addiction , 2016, Obesity.

[28]  Marcella Valente,et al.  Genetic Architecture of MAPT Gene Region in Parkinson Disease Subtypes , 2016, Front. Cell. Neurosci..

[29]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[30]  Keith A. Johnson,et al.  Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging , 2015, Neuropathology and applied neurobiology.

[31]  J. Haines,et al.  Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels , 2014, Alzheimer's Research & Therapy.

[32]  Robert C. Green,et al.  Variants in PPP3R1 and MAPT are associated with more rapid functional decline in Alzheimer's disease: The Cache County Dementia Progression Study , 2014, Alzheimer's & Dementia.

[33]  Wenyuan Xu,et al.  MAPT as a predisposing gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population , 2013, Neural regeneration research.

[34]  Constantinos Kallis,et al.  Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important? , 2011, Brain : a journal of neurology.

[35]  J. Kulisevsky,et al.  Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes. , 2011, Archives of neurology.

[36]  T. Gómez-Isla,et al.  The effect of MAPT H1 and APOE ε4 on transition from mild cognitive impairment to dementia. , 2011, Journal of Alzheimer's disease : JAD.

[37]  A. Fagan,et al.  SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease , 2010, PLoS genetics.

[38]  R. D. de Haan,et al.  The cognitive profile of amyotrophic lateral sclerosis: A meta-analysis , 2010, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[39]  Robert H. Brown,et al.  Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains , 2007, Acta Neuropathologica.

[40]  R. Wade-Martins,et al.  Functional MAPT haplotypes: Bridging the gap between genotype and neuropathology , 2007, Neurobiology of Disease.

[41]  S H Appel,et al.  Prevalence and patterns of cognitive impairment in sporadic ALS , 2005, Neurology.

[42]  A J Lees,et al.  Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration , 2005, Journal of Medical Genetics.

[43]  M. Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[44]  Nicholas W Wood,et al.  The structure of the tau haplotype in controls and in progressive supranuclear palsy. , 2004, Human molecular genetics.

[45]  D. Mann,et al.  Tau haplotype frequency in frontotemporal lobar degeneration and amyotrophic lateral sclerosis , 2003, Experimental Neurology.

[46]  B. Miller,et al.  Are amyotrophic lateral sclerosis patients cognitively normal? , 2003, Neurology.

[47]  T. Beach,et al.  Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick's disease, corticobasal degeneration and progressive supranuclear palsy , 2001, Acta Neuropathologica.

[48]  D. Geschwind,et al.  Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[50]  Daniela C. Zarnescu,et al.  Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases. , 2018, Advances in neurobiology.

[51]  Tao Li,et al.  A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x.cn) , 2009, Cell Research.

[52]  Fei Liu,et al.  Molecular Neurodegeneration BioMed Central Review Tau exon 10 alternative splicing and tauopathies , 2008 .