Study Of Association Between Tau Gene Polymorphisms In 5' UTR, 3' UTR And Introns With Familiy Amyotrophic Lateral Sclerosis

Objective:Analyse the location of Tau gene polymorphisms of 3′UTR, 5′UTR and intron in familial ALS and controls, combining with clinical data, and investigate initally the role of Tau gene polymorphisms in familial ALS. To find the possible pathogenesis of familial ALS, thus to provide theoretical basis and new ideas for the research of ALS with forward-looking diagnosis, prevention, treatment and prognosis.Methods:All subjects, patients and controls, were chinese. Patients with familial ALS(n=25) and controls(n=40), after informed consent, donated blood for research. DNA was extracted from leucocytes and amplified by PCR. The 3′UTR, 5′UTR and intronic SNPs were genotyped by PCR. All amplifed products were directly sequenced to analysis the tau gene polymorphisms, at last, do the statistical analysis and find the results.Results:1,Clinical description:The affected members were divided into two groups according to the progress of the disease:(1) Rapidly progressing group: MembersⅠ1,Ⅱ1,Ⅲ1,Ⅲ2,Ⅲ3 progressed rapidly with respiratory failure within 18 months after symptom onset. The mean duration of illness was 10.2 months, ranging from about 3 to 24 months. The mean age of symptom onset was 36.6 years old. They generally developed limb weakness at symptom onset, among the rapid progressive group, each patient were spinal onset, no one was bulbar onset. (2) Slowly progressive group: MembersⅡ3 developed slower progressive disease with limb weakness, with mainly lower motor neuron features, she developed bulbar symptoms after 3 years, eventually progressed with respiratory failure within at 4 years after symptom onset, but still alive now. The age of symptom onset was 60 years old, compared with rapidly progressing group, which was later and the duration of illness was longer. 2,The features of this FALS familiy history: (1) This family had affected members in three generation continuously, each affected members had an affected parents. (2) If neither of the parents were affected, the children also were not affected. (3) The affected boys and girls are eqully(1:1), no gender differences in the inheritance. (4) Any affected members had not yet appeared in the fouth generation.3,After the sequence alignment: we found 18 polymorphisms in the 3′UTR, 5′UTR and intron of tau gene(respectively is 135451 C>G,135504 C>G,135554 T>G,136491 G>T,138278 A>G,138300 A>G,138320 A>G,138325 C>G,138344 A>G,138380 T>G,138417 A>G,138418 T>G,102922 C>T,105646 G>A,105655 T>G,105697 T>G,107780 G>A,123972-123973 TC>AA或AC), the frequencies of the 18 polymorphisms in FALS group were higher than that in normal 40 controls, three of these polymorphisms which were 105697 T>G,138278 A>G,138417 A>G in FALS group compared to normal 40 controls showed a significantly higher frequency(p<0.05).(105697 T>G,138417 A>G polymorphisms used the Fisher exact test to analysis and P value were respectively 0.005,0.032; polymorphism 138278 A>G used Chi-square test to analysis and Chi-square value was 8.829,P value was 0.003.) However, the frequency of the other polymorphisms in the two groups showed no significant difference.4,Description and localization of tau gene polymorphisms: 75 of these nucleotide changes (56%) are found as two clusters in introns 9 and 10, a third cluster involving 22 nucleotide changes is observed in the 3′UTR. All polymorphisms we reported were single nucleotide polymorphisms(SNP).5,The three polymorphisms(105697 T>G,138278 A>G,138417 A>G) were significantly overrepresented only in the third and fouth generation of family members, who were not affected follow-up so far. However, in the affected members we have not found the three polymorphisms overrepresented.Conclusions:1,We found that the features of this family history were consistent with that of autosomal dominant inheritance disease. The affected members were divided into two groups according to the progress of the disease: (1) A group where progression occurred rapidly and developed respiratory failure within 18 months after symptom onset. (2) Another group where progression occurred more slowly after symptom onset.2,18 polymorphisms in the 3′UTR, and intron of tau gene: three polymorphisms of them in FALS group compared to normal 40 controls showed a significantly higher frequency(p<0.05), which indicated the three polymorphisms(105697 T>G,138278 A>G,138417 A>G) in the 3′UTR, and intron of tau gene were associated with the onset of FALS.3,The significantly overrepresented three polymorphisms have not found in the affected members, which indicated the three polymorphisms(105697 T>G,138278 A>G,138417 A>G) in the 3′UTR, and intron of tau gene were a risk gene, but not a pathogenic gene for FALS.