A novel mutation (K317M) in the
 MAPT
 gene causes FTDP and motor neuron disease

Zarranz, J.J.; Ferrer, Isidro; Lezcano, Elena; Forcadas, Maribel; Eizaguirre, B.; Atarés, Begoña; Puig, Berta; Gómez‐Esteban, Juan Carlos; Fernández-Maiztegui, C; Rouco, I.; Pérez-Concha, T.; Fernández, María Victoria; Rodriguez, Olga; Rodríguez-Martínez, Ana B.; Pancorbo, Marian M. de; Pástor, Pau; Pérez-Tur, Jordi

doi:10.1212/01.wnl.0000160116.65034.12

Cited by 93 publications

(84 citation statements)

References 46 publications

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“…MAPT mutations have been associated with pure FTD [16] and with FTD with parkinsonism and/or MND [7, 9, 11, 17], but also with progressive sopranuclear paralysis and Alzheimer disease [18, 19]. …”

Section: Discussionmentioning

confidence: 99%

“…Another association study by Fang et al [12] confirmed these findings and reported a higher incidence of breathing difficulties in sALS patients carrying specific MAPT genotypes. Moreover, in some studies, MAPT mutations have been reported to be associated with MND, although always in association with FTD [7, 9, 11]. …”

Section: Discussionmentioning

confidence: 99%

“…Due to the proven overlap between the ALS spectrum and frontotemporal dementia (FTD), the role of major ALS genes in the pathogenesis of both diseases is already well recognized, but the role of typical FTD genes in motor neuron diseases (MNDs) is less well known. In the past years, many single reports have outlined the role of the MAPT gene in familial FTD with motor neuron involvement [7-11], thus suggesting that tau protein may also have a role in motor neuron degeneration. Moreover, association studies have suggested that the MAPT gene could be a susceptibility gene for sALS both in European Caucasian patients [8] and in the Chinese Han population [12].…”

Section: Introductionmentioning

confidence: 99%

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Role of MAPT in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients

et al. 2018

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The aim of our study was to evaluate the role of mutations in the MAPT gene in patients with pure amyotrophic lateral sclerosis (ALS). A cohort of 120 ALS patients, both sporadic and familial, without cognitive impairment was analyzed by next-generation sequencing with a multiple-gene panel comprising 23 genes, including MAPT, known to be associated with ALS and frontotemporal dementia. The presence of the C9orf72 expansion was also investigated. Twelve patients had mutations in the SOD1, TARDBP, MATR3, and FUS genes, while 10 patients carried the C9orf72 expansion. One female patient was found to carry the D348G mutation in MAPT, previously reported in an Italian family with lower motor neuron disease. Our patient presented both upper and lower motor neuron signs, early development of dyspnea, resting and kinetic tremor, and a slow disease course (> 11 years). The present case further broadens the clinical phenotype associated with MAPT mutations and suggests that, although rarely, MAPT mutations can cause ALS and, therefore, should be analyzed in ALS patients, especially in those with early breathing difficulties and long-lasting disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of MAPT in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients

et al. 2018

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“…Various types of astrocytic inclusions are generated in familial FTLD-tau linked to mutations in exons 1 and 10 and in introns following exons 9 and 10, the morphology of which largely depends on the MAPT mutation. Intracytoplasmic tau-immunoreactive inclusions in FTLD-tau are represented by tufted-like astrocytes, astrocytic plaques, ramified astrocytes, TSAs, astrocytes with globular inclusions and other types with no specific names [17,33,34,36,37,66,[77][78][79][80][81][82][83][84][85][86]. Tufted astrocytes and astrocytic plaques practically do not co-exist in PSP and CBD [57], but these lesions appear in combination in FTLD-tau [29] (Figure 4).…”

Section: Introductionmentioning

confidence: 99%

Astrogliopathy in Tauopathies

Ferrer

2018

Neuroglia

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Astrocytes are involved in many diseases of the central nervous system, not only as reactive cells to neuronal damage but also as primary actors in the pathological process. Astrogliopathy is a term used to designate the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Astrocytopathy is utilized to name non-reactive astrogliosis covering hypertrophy, atrophy and astroglial degeneration with loss of function in astrocytes and pathological remodeling, as well as senescent changes. Astrogliopathy and astrocytopathy are hallmarks of tauopathies-neurodegenerative diseases with abnormal hyper-phosphorylated tau aggregates in neurons and glial cells. The involvement of astrocytes covers different disease-specific types such as tufted astrocytes, astrocytic plaques, thorn-shaped astrocytes, granular/fuzzy astrocytes, ramified astrocytes and astrocytes with globular inclusions, as well as others which are unnamed but not uncommon in familial frontotemporal degeneration linked to mutations in the tau gene. Knowledge of molecular differences among tau-containing astrocytes is only beginning, and their distinct functional implications remain rather poorly understood. However, tau-containing astrocytes in certain conditions have deleterious effects on neuronal function and nervous system integrity. Moreover, recent studies have shown that tau-containing astrocytes obtained from human brain tauopathies have a capacity for abnormal tau seeding and spreading in wild type mice. Inclusive conceptions include a complex scenario involving neurons, glial cells and local environmental factors that potentiate each other and promote disease progression in tauopathies.

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“…Additional, more detailed studies are needed to confirm whether mutations in TARDBP and FUS are indeed causative of "pure" FTD. Other genes associated with both ALS and FTD include MAPT, CHMP2B, DCTN1, ANG, DJ1, VCP, and PGRN (Annesi et al 2005;Munch et al 2005;Zarranz et al 2005;Mackenzie et al 2006;Parkinson et al 2006;van Es et al 2009a;Weihl et al 2009;Cox et al 2010;Johnson et al 2010). …”

Section: Genetic Correlation To Phenotype and Severity In Alsmentioning

confidence: 99%

Making Connections: Pathology and Genetics Link Amyotrophic Lateral Sclerosis with Frontotemporal Lobe Dementia

Fecto

Siddique

2011

J Mol Neurosci

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Over the last couple of decades, there has been a growing body of clinical, genetic, and histopathological evidence that similar pathological processes underlie amyotrophic lateral sclerosis (ALS) and some types of frontotemporal lobe dementia (FTD). Even though there is great diversity in the genetic causes of these disorders, there is a high degree of overlap in their histopathology. Genes linked to rare cases of familial ALS and/or FTD, like FUS, TARDBP, OPTN, and UBQLN2 may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS and ALS-FTD. Additionally, there are major loci for ALS-FTD on chromosomes 9p and 15q. Identification of causative genetic alterations at those loci will be an important step in understanding the pathogenesis of juvenile- and adult-onset ALS and ALS-FTD. Interactions between TDP-43, FUS, optineurin, and ubiquilin 2 need to be studied to understand their common molecular pathways. Future efforts should also be directed towards generation and characterization of in vivo models to dissect the pathogenic mechanisms of these diseases. Such efforts will rapidly accelerate the discovery of new drugs that regulate accumulation of pathogenic proteins and their downstream consequences.

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A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease

Abstract: Genetic analysis revealed the same novel mutation (K317M) in exon 11 of the MAPT gene in both pedigrees. A common haplotype between members of the two pedigrees suggests that they belong to the same family.

Cited by 93 publications

References 46 publications

Role of <b><i>MAPT</i></b> in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients

Role of <b><i>MAPT</i></b> in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients

Astrogliopathy in Tauopathies

Making Connections: Pathology and Genetics Link Amyotrophic Lateral Sclerosis with Frontotemporal Lobe Dementia

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