Positive association of CC2D1A and CC2D2A gene haplotypes with mental retardation in a Han Chinese population.

The CC2D1A and CC2D2A genes are involved in Ca(2+)-regulated signaling pathways and have recently been implicated in the etiology of mental retardation (MR). The aim of this study was to investigate whether CC2D1A and CC2D2A polymorphisms are associated with susceptibility to MR in a Han Chinese population using a family based association approach. The sample included 172 trios (parents and offspring), and all subjects were genotyped for several single-nucleotide polymorphisms covering CC2D1A and CC2D2A. Linkage disequilibrium (LD) analysis revealed that the rs6511901 and rs10410239 polymorphisms of CC2D1A were in strong LD (D'=0.865), and haplotype analysis showed evidence for over-transmission from parents to MR offspring (p=0.0009). The LD analysis also revealed that CC2D2A single-nucleotide polymorphisms rs10025837, rs13116304, and rs7661102 were in strong LD (D'=0.848), and haplotype analysis showed significant transmission disequilibrium (p=0.0004). The results suggest the involvement of CC2D1A and CC2D2A in MR in the Han Chinese population, and some specific haplotypes may be susceptible or protective.

[Progress on X-linked mental retardation related gene JARID1C].

JARID1C is one of the genes related to X-linked mental retardation. Its express product influences transcription and expression of the related genes in brain nervous system, and may be associated with human cognitive ability. Study on the functions of JARID1C not only helps to understand its molecular role in mental retardation and human cognitive ability, but also provides references for clinical diagnosis and prevention of mental retardation. This article reviews the progresses on JARID1C in location, isolation, physiological functions, and cognitive functions of its encoding product. The future re-search work of JARID1C is also discussed.

[Progresses on autosomal recessive nonsyndromic mental retardation related genes].

Some autosomal genes are associated with development and function of nervous system. Mutations of these genes can lead to nonsyndromic mental retardation. This paper reviews recent progresses on autosomal recessive nonsyndromic mental retardation related genes, including localization, expression, biological function and pathogenesis after mutations. The prospect in this field is also discussed.

[Anassociation study between OPHN1 gene rs492933 polymorphism and mental retardation in children of the Qinba Mountain region.].

The OPHN1 gene encodes a Rho-GTPase activating protein (RhoGAP), and mutations in OPHN1 are responsible for non-specific X-linked mental retardation (NSMR). A SNP located in the 5'-untranslated region (UTRs) of OPHN1 (rs492933) was examined by PCR-RFLP to assess its contribution to cognitive ability in 234 unrelated healthy and MR children in the Qinba Mountain region in Shaanxi. The allelic frequencies of rs492933 were 0.826 for the C allele and 0.174 for the T allele. Genotype frequencies and allelic frequencies were not significantly different between the MR and the controls, or between the borderline group and the controls. In conclusion, there is no association between the OPHN1 gene polymorphism and NSMR in the Qinba Mountain region children.

[Relationship between the polymorphisms of GDI1, children NSMR and their intelligence in Qinba region].

The subjects of this study were recruited from Zha Shui and An Kang counties in the Qinba mountain region located in Middle-west China. The present study discussed the relationship between the variations of GDI1 with the children NSMR and their intelligence levels. The case-control association analysis method was used to analyze the association between the polymorphisms of two functional SNPs (rs2276462 and rs11549300) located in splicing site of the seventh exon and the eighth exon respectively, with NSMR and their different intelligence levels. It does not find out the polymorphism of rs2276462, because of its conservation. The results of case-control analysis indicated that, no association between the rs11549300 polymorphisms and children NSMR (P >0.05), but its polymorphisms may be related to intelligence levels of children in Qinba region (P =0.03). And a further work should be done to verify the conclusion of this study using the more genetic markers of GDI1 in a larger sample.

[Research progress on nonsyndromic X-linked mental retardation related gene PAK3].

Mutations of the gene coding for PAK3 (p21-activated kinase 3) are associated with nonsyndromic X-linked mental retardation (MRX). It may be associated with generalized or specific cognitive ability. Studying the biological and cognitive function of PAK3 is important for MR diagnosis and prevention. This paper reviews the progress on PAK3 including its gene product, biological and cognitive function. The future directions on the study of PAK3 are also discussed.

[Polymorphism of CGG repeats in the FRAXE fragile site in the Qinba Mountain area children and its association with intelligence].

Variations of CGG repeats in the FRAXE fragile site were determined by PCR amplification followed by polyacrylamide gel electrophoresis and sequencing in randomly collected Qinba Mountain Area children whose intelligence level was determined by China-Wechsler Intelligence Scale for Children (C-WISC). Correlations between IQ score and the number of CGG repeats were analyzed. Results indicated a difference in the range of CGG repeats among populations from different regions, but no difference in the distribution of allele frequency in such a population. CGG repeats were not associated with IQ scores in randomly collected subjects (r=0.083, P>0.05), in males and females (r(m)=0.225, r(f)=-0.041, P>0.05), or in subjects with different intelligent levels (F=0.195, P>0.05). It can be inferred that variation in the size of CGG repeats was not associated with intellectual performance in the Qinba Mountain area children.

Association between a functional COMT polymorphism, mental retardation and cognition in Qinba area children.

Catechol-O-methyl transferase (COMT) plays an important role in the metabolism of neurotransmitters. Two alleles of the COMT gene as a result of a G/A transition in the exon 4 can lead to different COMT enzymatic activities. Much genetic research has revealed that this COMT functional polymorphism was related to human psychiatric disorders. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods were used to discern the relationships among the functional polymorphism of COMT, mental retardation (MR), and general cognitive ability of children. The results of the case-control analysis showed that there was no association between the frequencies of genotypes of COMT and MR (chi2=0.776, P>0.05) or between the frequency of COMT alleles and MR (chi2=0.335, P>0.05). COMT polymorphism was found in children whose intelligence quotient (IQ) was above 55. In normal children (IQ> or =85), the frequencies of high-activity allele COMTH and the homozygote genotype COMTHH were 60.98% and 79.28%, respectively. Both were higher than those of the borderline group (46.67% and 70.67%, 0.10 > P>0.05). Therefore, the result of this study suggests that this functional polymorphism is not an important risk factor for MR, but the COMTHH genotype may have a positive effect on cognitive performance in normal children in the Qinba area.

[Progress of functional study on MRX related genes].

X-linked nonspecific mental retardation (MRX) related genes are a group of extensively studied genes whose mutation or deletion results in simple phenotypes of generalized or specific cognitive impairment in patients, such as, low intelligence and poor social adaptability. Studying the biological and cognitive functions of MRX related genes means much not only to the discovery of the genetic basis for non-specific MR, but also to the exploration into a new field of research about the molecular basis of human cognitive function. This paper summarizes recent progress on MRX studies, the current status and the prospect of this field.

An association study between the transthyretin (TTR) gene and mental retardation.

It is known that in the pathogenesis of mental retardation (MR), both genetic and environmental factors (particularly iodine deficiency) appear to play a critical role. Transthyretin (TTR) transports between 20% and 30% of serum thyroxine in normal individuals and it is the main T(4)-binding protein in CSF. Variability in the TTR gene may influence risk for iodine-deficiency-based MR. The SNPs we selected from dbSNP were detected and identified using ARMS-PCR and sequencing methods, and we identified five novel sequence variants. Singular-locus association analysis indicated no association between the TTR gene and MR. In haplotype analysis, however, we found a haplotype CGTG+ (rs723744/G+6649C/T+6690C/rs2276382/del9) showed a weak positive association with MR (chi(2) = 6.699, p = 0.035). Finally, we concluded that the weak positive result is more likely to be due to sampling error and the small size of this haplotype resulting from its relative low frequency. Our negative results provide no evidence that variants of TTR gene influence susceptibility to MR in the iodine-deficient areas of China and suggest that there may be a compensatory mechanism(s) in humans and mice, which work(s) to compensate the effect of mutation in the TTR gene on MR.

Polymorphisms in the TSHR (thyrotropin receptor) gene on chromosome 14q31 are not associated with mental retardation in the iodine-deficient areas of China.

Mental retardation (MR) is one of the most frequent handicaps among children. Fetal iodine deficiency disorder (FIDD) is the commonest cause of preventable MR. However, not everyone in the iodine-deficient areas is affected and familial aggregation is common. This suggests that genetic factors may play an important role. Thyroid hormone (TH) plays an important role in fetal and early postnatal brain development. The thyroid-stimulating hormone (TSH, or thyrotropin) receptor (TSHR) is located on the surface of thyroid cells and binds TSH. It results in the production of thyroid hormones via the activation of adenylate cyclase and phospatidylinositol-dependent signaling pathways. Some researchers formulated the hypothesis that TSH receptor expression in the brain may be involved in local thyroid homeostasis through TSH stimulating the DIO2 activity. In the previous study, we have proposed that DIO2 may protect against FIDD in the iodine-deficient areas of China. The TSHR gene, which located on chromosome 14q31 is a potential candidate gene for susceptibility to FIDD. To investigate the potential genetic contribution of TSHR gene, we performed a case-control association study in Chinese Han population from the Qin-Ba mountain regions using four common SNPs in the gene (rs2284716, rs917986, rs2075173 and rs2075179). Pairwise linkage disequilibrium (LD) analysis showed that LD was observed between rs2284716 and rs917986 and between rs2075173 and rs2075179. Single-locus analysis found that all four SNPs in TSHR gene showed no association after correction for multiple testing. Haplotype analysis showed no significant differences in frequency for three sets of haplotypes based on the pariwise LD results. In conclusion, our association results suggest that TSHR gene is not a susceptibility gene for FIDD in the iodine-deficient areas of China.