Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.

FUS mutations in sporadic amyotrophic lateral sclerosis: Clinical and genetic analysis

“…All previously described p.P525L mutation carriers showed an aggressive course of the disease and no family history has been documented in any previous studies (Bäumer et al, 2010;Chiò et al, 2009;Kwiatkowski et al, 2009). The clinical pattern observed in patient ALS-03 (young age at onset at 26 years and rapid progression causing death within 12 months), is similar to that already reported for this mutation, confirming that the p.P525L substitution results in a highly aggressive form of ALS.…”

“…Much evidence suggests that mutations in FUS are associated with earlier onset of ALS than the general mean age of approximately 60 years (Corrado et al, 2010;Kwiatkowski et al, 2009;Vance et al, 2009). …”

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

“…Over 35 mutations have been described in FUS, which has been identified as the primary cause of ALS type 6 (Vance et al, 2009). In healthy controls this multifunctional protein, with roles ranging from DNA repair, transcriptional regulation and mRNA transport (Lagier‐Tourenne, Polymenidou, & Cleveland, 2010), is located primarily in the nucleus (Dormann et al, 2010); however, post mortem tissues of FUS‐ALS patients reveal cytoplasmic inclusions in affected neurons and glia (Kwiatkowski et al, 2009). Specifically, carriers of the FUS R521C, R521G, R521H, R524W, or G507N mutations show wide‐spread FUS pathology (Blair et al, 2009; Hewitt et al, 2010; Rademakers et al, 2010), including glial and neuronal cell loss, with increasing distribution of FUS‐immunoreactive inclusions in patients with longer disease durations (Suzuki et al, 2012).…”

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

“…Mounting genetic evidence suggests that motor neuron degeneration in ALS represents a final common pathway initiated by ≥1 conserved upstream mechanisms, including protein misfolding/aggregation [5][6][7][8][9][10][11][12], RNA misprocessing [10,[13][14][15][16][17][18][19], and disruptions in axonal transport [12,[20][21][22][23][24]. These mechanisms are not mutually exclusive, and instead may enhance one another, thereby accentuating neurodegeneration in ALS.…”

“…The identification of neuronal cytoplasmic inclusions rich in the RNA-binding protein transactive response element DNA/RNA binding protein of 43 kDa (TDP43) provided an important link between two of these mechanisms-protein aggregation and RNA dysfunction [6,7]. TDP43-positive inclusions are a hallmark of sporadic ALS (sALS) and the majority of fALS [6,7,25,26], and mutations in the genes encoding TDP43 (TARDBP) and related RNA binding proteins [15,16,19,27,28] cause fALS, emphasizing the critical importance of RNA processing to the pathogenesis of both sALS and fALS. TDP43 is a member of the heterogenous nuclear ribonuclear protein (hnRNP) family of RNA binding proteins that have diverse and integral functions in RNA metabolism and homeostasis [29].…”