FUS And TARDBP Mutations In Amyotrophic Lateral Sclerosis Cases From China

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. ALS is a kind of complex disease contributed by multiple genetic and environmental factors. Ten percent of cases have a familial history. Ubiquitinated protein aggregates in the cytoplasm is the hallmark of ALS as many other neurodegenerative disease. Recent researches have showed that the main component of these abnormal inclusions are transactive response DNA binding protein (TARDBP) and fused in sarcoma protein (FUS). Many mutations of these two genes have been reported. The structural and functional similarities of TARDBP and FUS, which are both DNA/RNA binding proteins, suggest that abnormal RNA metabolism may be one of the pathogenic mechanisms of ALS.OBJECTIVE:To determine the frequency of FUS and TARDBP mutations in a cohort of ALS cases from China.METHODS:We recruited7familial ALS (FALS) families,137sporadic ALS (SALS) cases and90matched controls for our study. Genomic DNA was extracted form whole blood samples. The coding region of FUS exon14,15and TARDBP exon6were amplified by polymerase chain reaction (PCR). The PCR products were sequenced by company.RESULTS:1. We observed3single nucleotide changes in FUS and all of them were heterozygous. A missense mutation (p.Arg521Leu, c.G1562T) was observed in a FALS. A synonymous mutation (c.C1464T) was observed in a SALS case. The third mutation c.C1595T, which was behind the stop codon, was observed in a SALS case. These nucleotide changes were not observed in the controls.2. The TARDBP exon6of65SALS cases in the137were sequenced by Dr. Lin previously. Among the others we observed one heterozygous missense mutation (p.Gly348Val, c.G1043T) in a SALS case. This mutation was not observed in the controls.CONCLUSIONS:1. Mutations in FUS account for14.3%(1of7) of FALS and0%of SALS in our Chinese cohort. The frequency of FUS mutation in our Chinese FALS is equal to that reported in Asia cohorts, and the frequency of Asia cohorts is obviously higher than European and North American cohorts.2. Mutations in TARDBP account for0%of FALS and0.69%(1of137) of SALS in our Chinese cohort, which is similar to the frequency reported by other cohorts.