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FUS G559A Mutation in a Patient with a Frontotemporal Dementia-Motor Neuron Disease Compatible Syndrome: A Case
Russell H Swerdlow1,2,3,4, Omar Jawdat2, Liskin Swint-Kruse4
1University of Kansas Alzheimer's Disease Research Center, University of Kansas Medical Center, Kansas City, KS, USA.
Abstract:
Fused in sarcoma (FUS) mutations cause frontotemporal dementia (FTD) and motor neuron disease (MND). Here, we describe a 43-year-old man with progressive behavioral and cognitive change, myelopathy, clinical and electrophysiologic evidence of MND, and a FUS variant of unknown significance (VUS). This VUS, a heterozygous G559A transition (Gly187Ser), was previously reported in a patient with sporadic MND and affects important FUS biophysical properties. While this rare variant's presence in a second patient with a related neurodegenerative syndrome does not establish pathogenicity, it raises the question of whether its association with our patient is coincidental and increases the possibility that FUS G559A is pathogenic.
Insights
Fused in sarcoma (FUS) mutations are linked to frontotemporal dementia (FTD) and motor neuron disease (MND). A rare FUS gene variant (G559A) was found in a patient with FTD/MND symptoms, raising questions about its pathogenicity.
Area of Science:
- Neurogenetics
- Molecular Neurology
Background:
- Mutations in the Fused in Sarcoma (FUS) gene are established causes of neurodegenerative disorders, including frontotemporal dementia (FTD) and motor neuron disease (MND).
- The clinical and pathological spectrum associated with FUS mutations is diverse, highlighting the gene's critical role in neuronal function and survival.
Observation:
- A 43-year-old male presented with progressive behavioral and cognitive decline, myelopathy, and clinical/electrophysiological evidence consistent with MND.
- Genetic analysis revealed a heterozygous FUS variant of unknown significance (VUS): G559A (Gly187Ser).
Findings:
- This specific FUS G559A variant was previously identified in an unrelated patient with sporadic MND.
- The G559A variant has been shown to alter critical biophysical properties of the FUS protein.
- The recurrence of this VUS in a second patient with a related neurodegenerative syndrome warrants further investigation into its pathogenic potential.
Implications:
- The presence of the FUS G559A variant in two unrelated individuals with FTD/MND-like syndromes increases the suspicion of its pathogenicity.
- Further functional studies are needed to definitively establish the role of the FUS G559A variant in neurodegeneration.
- This case underscores the importance of evaluating variants of unknown significance in the genetic diagnosis of complex neurological disorders.
