Abstract
Objective: Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of motor neurons. Mutations in the FUS gene were identified in patients with familial ALS (FALS) and patients with sporadic ALS (SALS) from a variety of genetic backgrounds. This work further explores the spectrum of FUS mutations in patients with FALS and patients with FALS with features of frontotemporal dementia (FALS/FTD) or parkinsonism and dementia (FALS/PD/DE). Methods: All exons of the FUS gene were sequenced in 476 FALS index cases negative for mutations in SOD1 and TARDBP. A total of 561-726 controls were analyzed for genetic variants observed. Clinical data from patients with FUS mutations were compared to those of patients with known SOD1 and TARDBP mutations. Results: We identified 17 FUS mutations in 22 FALS families, 2 FALS/FTD families, and 1 FALS/PD/DE family from diverse genetic backgrounds; 11 mutations were novel. There were 4 frameshift, 1 nonsense, and 1 possible alternate splicing mutation. Patients with FUS mutations appeared to have earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms than those with SOD1 mutations. Conclusions: FUS gene mutations are not an uncommon cause in patients with FALS from diverse genetic backgrounds, and have a prevalence of 5.6% in non-SOD1 and non-TARDBP FALS, and ∼4.79% in all FALS. The pathogenicity of some of these novel mutations awaits further studies. Patients with FUS mutations manifest earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 807-814 |
| Number of pages | 8 |
| Journal | Neurology |
| Volume | 75 |
| Issue number | 9 |
| DOIs | |
| State | Published - Aug 31 2010 |
Funding
Dr. Yan and Dr. Deng report no disclosures. N. Siddique receives salary support from the NIH (NINDS NS050641 [research nurse]) and the Les Turner ALS Foundation. Dr. Fecto, Dr. Chen, Y. Yang, and Dr. Liu report no disclosures. S. Donkervoort receives research support from the NIH (NINDS NS050641). Dr. Zheng, Dr. Shi, and K.B. Ahmeti report no disclosures. Dr. Brooks serves/has served on scientific advisory boards for Avanir Pharmaceuticals and Sanofi-Aventis and receives research support from Avanir Pharmaceuticals, Carolinas ALS Research Fund, and Harris Research Fund–Carolinas Healthcare Foundation. Dr. Engel reports no disclosures. Dr. Siddique serves on the scientific advisory board of NIH: Skeletal Muscle and Exercise Physiology (SMEP) Study Section; serves on the editorial boards of Neurogenetics and Amyotrophic Lateral Sclerosis ; holds a patent re: Human alpha-tocopherol transport protein: compositions and methods; and receives research support from the NIH (NINDS RO1 NS046535 [PI], NINDS RO1 NS050641 [PI], NIEHS-RO1 ES014469 [PI], NIEHS PO1 ES016742 [PI]), the Harold Post ALS Research Fund, the Les Turner ALS Foundation/Herbert C. Wenske Foundation, Vena Schaaf, Frank White ALS Research Fund, the Spastic Paraplegia Foundation, Inc., the Amyotrophic Lateral Sclerosis Association, the CVS/ALS Therapy Alliance, and the Blazeman Foundation for ALS.
ASJC Scopus subject areas
- Clinical Neurology