[Objective]To investigate the genetic polymorphisms of the CYP2C19 gene in the elderly Chinese Han populations of Guangzhou,and compare the frequencies of CYP2C19 gene polymorphisms in different populations,in order to provide accurate data for the appropriate prescription.[Methods]To detect the genetic polymorphisms of the CYP2C19 gene by the DNA microarray,and compare the frequencies of CYP2C19 gene polymorphisms in Chinese Han populations from different areas and the different races.[Results]There were 2312 case samples in our study. The allele frequencies of CYP2C19*1,CYP2C19*2 and CYP2C19*3 were 64.27%,30.75%,and 4.98%,respectively. As the genotype,EM(*1/*1)was 41.44%(n=958),IM(*1/*2,*1/*3)was 45.67%(n=1056),and PM(*2/*2,*2/*3 and*3/*3)was 12.89%(n=298). The ratios of EM and IM in Chinese Han populations from different areas and all the subtypes of the CYP2C19 genotype in different minority were statistically significant. As the races,there were difference in all the subtypes of the CYP2C19 genotype when Asian populations were compared with white races(P<1304.64)and black races(P<0.01),which was also statistically significant.[Conclusions]The distributions of the CYP2C19 gene polymorphisms were significantly different in Chinese han populations and in different races,and the main subtypes of the CYP2C19 genotype in the elderly of Chinese han populations were IM and EM,which is beneficial for prescribing appropriate in the elderly populations.

Objective To conduct mutation screening of SCN1A 3′ untranslated region (UTR) on Dravet syndrome (DS) patients without mutations in the SCN1A coding region and promoter region, and functional analysis of the variant from DS patients.Methods Twenty-eight DS patients without mutations in the SCN1A coding region and promoter region were screened for SCN1A 3′ UTR mutations using PCR and direct sequencing.Functional analysis of the detected mutation was done via luciferase assay, mRNA stability analysis and RNA electrophoretic mobility shift assay (RNA-EMSA).Results A novo variant (c.*20A>G) in SCN1A 3′ UTR was found in one DS patient.The variant (c.*20A>G) reduced the luciferase gene xpression by 30% through increasing the affinity of pluripotent embryonal carcinoma cell line NT2/cytoplasmic protein binding and reducing luciferase gene mRNA stability (t=8.5,P<0.01).Conclusions A functional variant was detected from one patient with DS.This variant negatively regulated the gene expression by increasing the affinity of pluripotent embryonal carcinoma cell line NT2/cytoplasmic protein binding and reducing mRNA stability.

Auditory neuropathy spectrum disorder (ANSD) represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function, but with the preservation of outer hair cell function. ANSD represents up to 15% of individuals with hearing impairments. Through mutation screening, bioinformatic analysis and expression studies, we have previously identified several apoptosis-inducing factor (AIF) mitochondria-associated 1 (AIFM1) variants in ANSD families and in some other sporadic cases. Here, to elucidate the pathogenic mechanisms underlying each AIFM1 variant, we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and constructed AIF-wild type (WT) and AIF-mutant (mut) (p.‍T260A, p.‍R422W, and p.‍R451Q) stable transfection cell lines. We then analyzed AIF structure, coenzyme-binding affinity, apoptosis, and other aspects. Results revealed that these variants resulted in impaired dimerization, compromising AIF function. The reduction reaction of AIF variants had proceeded slower than that of AIF-WT. The average levels of AIF dimerization in AIF variant cells were only 34.5%‍‒‍49.7% of that of AIF-WT cells, resulting in caspase-independent apoptosis. The average percentage of apoptotic cells in the variants was 12.3%‍‒‍17.9%, which was significantly higher than that (6.9%‍‒‍7.4%) in controls. However, nicotinamide adenine dinucleotide (NADH) treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells. Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD, and introduce NADH as a potential drug for ANSD treatment. Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.
Humans ; Apoptosis Inducing Factor/metabolism* ; NAD/metabolism* ; Dimerization ; Apoptosis