Mutation Study Of Predisposing Genes For Psoriasis And Autism

Chapter 1. Mutation analysis of FLG gene in Chinese Han psoriasis patientsPsoriasis [OMIM 177900] is a common chronic inflammatory dermatosis, clinically characterized by red raised patches covering with white scale on the skin and pathologically characterized by abnormal differentiation in epidermal layers(hyperkeratosis, parakeratosis, stratum granulosum attenuation or disappearance, and acanthosis) and inflammation(intercellular space widen, inflammatory cell infiltration of the dermis and dermal vessel dilatation). By investigating, current prevalence are 0.6-4.8% worldwidely, and 10 million psoriasis patients exist in China. The usual age of onset of psoriasis is between 15 and 30 years and then usually persists for life. Psoriasis is a kind of polygenic disease, and the pathogenesy of psoriasis is so complicated that is still elusive. By affecting immune system, inflammation pathway,the epidermal barrier,various of genetic and environmental factors cause psoriasis. Smoking, drinking, psychentonia and physical injuries and so on are also the triggering factors.FLG gene, which encodes filaggrin, is located within the epidermal differentiation complex (EDC) on 1q21.3 and expressed late in epidermal differentiation. Keratohyalin granules in the granular layer are predominantly composed of phosphorylated and insoluble protein profilaggrin. Keratohyalin granules in the granular layer are predominantly composed of the phosphorylated and insoluble protein profilaggrin. Loss-of-function FLG mutation leads to abnormal differentiation (hyperkeratosis, parakeratosis) in epidermal layers and cause relative dermatosis。FLG gene is identitied to cause ichthyosis vulgaris first. Resently, it is reported that FLG gene also cause Atopic Dermatitis. Immunohistochemical analysis revealed a markedly reduction of filaggrin expression in psoriatic skin.2 psoriasis Chinese Han psoriasis/ ichthyosis vulgaris families,328 sporadic unrelated Chinese Han patients with psoriasis and 500 controls were involved in our study. By long range PCR and direct sequencing we analyze the FLG gene of the psoriasis patients and the health individuals,we identified a nonsense mutation, K4022X, in the family 1. The proband(Ⅲ:2) carries homozygous nonsense mutation, K4022X. TheⅣpatients (Ⅰ:4,Ⅱ:6)carry heterozygous nonsense mutation, K4022X. Besides, four health members (Ⅰ:2,Ⅱ:1,Ⅱ:4,Ⅱ:5)carry heterozygous nonsense mutation, K4022X. We identified 2 of 328 cases carry homozygous nonsense mutation, K4022X, and 22 of 328 cases carry heterozygous nonsense mutation, K4022X. We identified 15 of 500 controls carry heterozygous nonsense mutation, K4022X. By statistical analysis, we obtain allele frequencies:χ2=12.56,ν=1, P<0.005; genotype frequencies:χ2=16.76,ν=2, P<0.005; the OR(odds ratio)=2.855,95% CIs(Confidence Intervals)=2.275-9.974. We did not found any FLG mutation in the family 2.According to the studies aboved, the nonsense mutation, K4022X, may lead to the onset of the psoriasis in the family 1. May any other gene mutation exists in the family 2 to cause psoriasis. The allele frequency of the nonsense mutation, K4022X, is 1.5% in Chinese Han People. K4022X is a kind of common FLG mutation related to abnormal differentiation in epidermal layers.Chapter 2. Mutation analysis of NLGN3/4/Y gene in Chinese Han autism patientsAutism [OMIM 209850] is a severe childhood neurodevelopmental disorder. The onset of autism is before 3 years of age. The prevalence reported is increasing year by year. By investigating, current prevalence are 0.6% worldwidely and 0.1% in China. Males are affected by autism approximately 4 times more frequently than females. The main clinical character is impairment of social and communication skills, repetitive and stereotypical behaviors, restricted range of interests.The etiology of autism is still unknown. However, by investigating, autism is a complex disease with high heritability. Cytogenetics study showed that it has a high incidence of chromosome abnormality. Many related loci and several predisposing genes have been identified by sibling, family study, case-control association study, Genome-wide association study(GWAS) and so on.It is demonstrated that the abnormal neuronal synapse is related to autism. Neuroligins are postsynaptic cell adhesion molecules, by forming heterotetramer with presynaptic cell adhesion molecules neurexins, regulate the fine balance between excitation and inhibition of the synapse. In humans, the neuroligin protein family comtain five genes, NLGN1,2, 3,4 and 4Y. It is reported the NLGN3/4 mutations cause autism. However, no study on NLGNs and autism have done in Chinese Han people.318 sporadic unrelated Chinese Han patients with autism were involved in our study. By routine PCR and direct sequencing we analyze the NLGN3/4/Y genes of the autism patients.we identified a samesense mutation c.1638G>A and 1 missense mutations G406S in NLGN3 and a samesense mutation c.1194C>T and 3 missense mutations G84R,Q162K and A283T in NLGN4. All the 6 mutations have not been identified in 278 controls.These mutations in NLGN3/4 may cause autism. The NLGN3/4 mutations can cause autism in different race of people. Maybe other gene mutations exist in the patients.