Transmission Disequilibrium Analysis Of 1137-1140 Del GTGA Frameshift Mutation Within The KCNN3 Gene Using Family Trios With Schizophrenia

Background and Objective: KCNN3 gene encodes hKCa3, a human small conductance calcium-activated potassium channel, which is expressed in the central nervous system and modulates the firing pattern of neurons by generating slow membrane after-hyperpolarization. Chandy(1998) isolated and mapped KCNN3 gene to chromosome 1q21, found that longer CAG repeats in KCNN3 gene were associated with schizophrenia and suggested that KCNN3 gene could be a positional candidate gene for schizophrenia. Bowen(2001) detected a 4-bp deletion 1137-1140 GTGA in exon 1 with KCNN3 gene in a schizophrenic patient. The 1137-1140 Del GTGA changes the open reading frame and results in frameshift mutation and translating a truncated protein(skCa3 - 1/285). Using confocal microscopy and whole-cell patch clamp recording, Miller(2001) observed skCa3 - 1/285 localization rapidly and exclusively to the nucleus of mammalian cells and skCa3 - 1/285 might co-assemble with normal skCa subunits encoded by all three loci in these gene family and suppress all endogenous skCa currents in a dominant-negative mechanism in human Jurkat T cell. Miller proposed that the nuclear localization of skCa3-l/285 may alter the neuronal architecture and the ability of skCa3-l/285 todominantly suppress endogenous small conductance kCa currents may affect patterns of neuronal firing. These two effects may play a part in the pathogenesis of schizophrenia and other neuropsychiatric disorders. However, No hypothesis has been reported yet. We conducted a study among Han Chinese in south China Guangdong. The purpose was to investigate an association of 1137-1140 Del GTGA in exon 1 at KCNN3 gene with schizophrenia.Material and Methods: The study includes 289 subjects (affected 107;unaffected 182) from 95 core pedigrees . All subjects were collected from Han Chinese in South China and genotyped for 1137-1140 Del GTGA in KCNN3 using PCR and restriction endonuclease D del . The genotypes were expressed with A₁A₁ (Ins/Ins homozygote), A₁A₂(Ins/Del heterozygote) and A₂A₂ (Del/Del homozygote) for 1137-1140 Del GTGA in KCNN3 gene. All the affected patients met the CCMD- II -R criteria for schizophrenia. The Positive and Negative Syndrome Scale (PANSS) was used for clinical assessments. The haplotype-based haplotype relative risk(HHRR) and transmission/disequilibrium test(TDT) analyses were done in 95 core pedigrees.Results: There were 1 A₂A₂ genotypes, 26 A₁A₂ genotypes and 80 A₁A₁ genotypes in schizophrenia and 1 A₂A₂ genotypes, 40 A₁A₂ genotypes and 141 A₁A₁ genotypes in non schizophrenia. Comparing the distribution of alleles between affected and unaffected parents(87 family trios) showed no significant difference ((x²=0. 253, P>0. 05).HHRR showed that KCNN3 gene alleles transmitted to the patients were not different from that of the non-transmitted parental alleles ( x¹=0. 0244, P>0. 05). TDT revealed that A₂alleles was not preferentially transmitted to schizophrenic patients ( x²=3. 000, P=0. 0833).Comparison between (A₁A₂ + A₁A₂) and (A₁A₁) genotypes for affected subjects revealed no significant association between diagnosis isoforms and all PANSS factor items.Conclusions:1. There was a lower frequency for 1137-1140Del homozygote of KCNN3 gene in our study.2. The HHRR and TDT analyses suggested that 1137-1140 Del alleles of KCNN3 gene may not associated with schizophrenia in our study.3. There was no association of the genotype of 1137-1140 Del in KCNN3 with schizophrenic phenotype.