Fus gene mutations in familial and sporadic amyotrophic lateral sclerosis

Abstract

Mutations in the fused in sarcoma (FUS) gene have recently been found to cause familial amyotrophic lateral sclerosis (FALS). We screened FUS in a cohort of 200 ALS patients [32 FALS and 168 sporadic ALS (SALS)]. In one FALS proband, we identified a mutation (p.R521C) that was also present in her affected daughter. Their clinical phenotype was remarkably similar and atypical of classic ALS, with symmetric proximal pelvic and pectoral weakness. Distal weakness and upper motor neuron features only developed late. Neuropathological examination demonstrated FUS-immunoreactive neuronal and glial inclusions in the spinal cord and many extramotor regions, but no TDP-43 pathology. We also identified a novel mutation (p.G187S) in one SALS patient. Overall, FUS mutations accounted for 3% of our non-SOD1, non-TARDBP FALS cases and 0.6% of SALS. This study demonstrates that the phenotype with FUS mutations extends beyond classical ALS cases. Our findings suggest there are specific clinicogenetic correlations and provide the first detailed neuropathological description.

FIGURE 1

Sequence chromatograms of the c.1561C>T (p.R521C) and c.559G>A (p.G187S) mutations (A). Pedigree of the family carrying the c.1561C>T (p.R521C) mutation in FUS (B). Evolutionary conservation of the p.G187S mutation (C) and p.G173_G174del deletion (D) in FUS generated by MUSCLE. The mutated amino acids are shown in red.

FIGURE 2

Post-mortem neuropathology in a case of familial ALS with a FUS mutation. Normal myelin staining of corticospinal tracts (A). Lower motor neurons contained FUS-immunoreactive cytoplasmic inclusions with granular (B), filamentous (C) or compact (D) morphology. Note that some neurons with inclusions retained normal nuclear FUS staining (arrow, B). Many glial cells also contained FUS-immunoreactive cytoplasmic inclusions (E). FUS-immunoreactive pathology was present in many neuroanatomical regions other than the pyramidal motor system, such as the substantia nigra (F). (A) Hematoxylin and eosin/luxol fast blue, (B-F) FUS immunohistochemistry. Scale bar: A, 250 μm; B, C and F, 30 μm; D and E, 20 μm.