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

Abstract

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.

Adult-onset non-5q proximal spinal muscular atrophy: a comprehensive review

“…None of the patients presented with signs suggestive of frontotemporal lobar degeneration or its variants 64 . This same gene mutation was identified also in an Italian female patient with LMN-dominant ALS with long-lasting disease course, mild Parkinsonism, and early respiratory failure 65 . This clinical-genetic subtype added intraneuronal tau degradation and its related pathways to the pathophysiological understanding of lower motor neuron degeneration and the potential role of neurofibrillary tangles with hyperphosphorylated tau protein as potential neuropathological biomarkers of this non-5q SMA.…”

Analysis of DNA methylation profiles during sheep skeletal muscle development using whole-genome bisulfite sequencing

“…Importantly, the mRNA expression of ADI-POQ may determine the responses of follicular to gonadotropins, thereby inducing ovum release. Mutations in the MAPT gene are associated with amyotrophic lateral sclerosis [36], while skeletal muscle autophagy can be regulated through MAPT [37]. NR4A1, a transcription factor, was shown to regulate the expression of genes involved in wasting the mitochondrial energetic budget and activating the AMPK catabolic pathway [38].…”

Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease‐linked MATR3 mutations in Drosophila

“…Tau is a microtubule-associated protein that is involved in microtubule assembly and stability [68,69]. Mutations in MAPT have been identified in FTD, motor neuron disorders [70][71][72], and ALS [26,73]. Knockdown of Tau may enhance mutant MATR3 toxicity by dysregulating axonal transport, thereby leading to further buildup of mutant MATR3.…”

“…Over a dozen missense or splicing mutations in MATR3 have been identified in ALS and myopathy patients (ALS21 OMIM #606070) [23][24][25][26][27][28]. Since these mutations do not reside in the functional domains of MATR3, it is difficult to predict how they might affect MATR3 function.…”