The Mutation Analysis Of GJB3and GJB4Gene In A Family With Erythrakeratodermia Variabilis

Background Erythrokeratodermia variabilis (EKV, MIM133200) is a rare congenitaldisease of keratinization, which is usually inherited in an autosomal dominant model. Itis characterized by migratory erythematous patches and fixed hyperkeratotic plaques.The erythematous patches may be geographic, circinate, gyrate or target-like, and varyin shape, size and sites during a few hours to days. The hyperkeratotic plaques are stableand well-demarcated, often involving the extensor of limbs, buttocks and face.Approximately50%of EKV patients display a palmoplantar keratoderma (PPK). Thedisorder usually starts shortly after birth or during the first year of life. Most cases ofEKV usually worsen until puberty and then enter a stable and chronic course all the life.The disease may be triggered by internal and external factors including stress, suddentemperature changes, mechanical friction, traumas, pregnancy, sun exposure,anticoncipiens and so on. The deleterious mutations in GJB3and GJB4genes areresponsible for EKV. The GJB3and GJB4genes in the chromosome1p34-35encodethe gap junction protein connexin31(Cx31) and connexin30.3(Cx30.3) respectively.Both Cx31and Cx30.3mediating intercellular communication are crucial for epidermaldifferentiation. The epidermal differentiation and function were disturbed becausevarious pathogenic missense mutations in GJB3and GJB4gene leading to EKV. To date,a total of thirteen mutations in the GJB3gene and seven mutations in the GJB4genehave been identified respectively, including only three recessive cases caused byhomozygous mutations in GJB3gene.Objective (1) To search for the mutations of GJB3and GJB4gene in a Chinese Han EKV pedigree.(2) To summarize the genotype-phenotype correlation in the disease.Methods Blood samples were collected for DNA extraction from the proband and hisparents after informed consent were obtained. One six hundred and sixty sevenunrelated blood samples from normal individuals were collected as controls. Weamplified the entire coding regions of the GJB3and GJB4gene by polymerase chainreaction (PCR) and sequenced the purified PCR products by ABI3730XL automatedsequencer. We review all the mutations with EKV in the literature to summarize thegenotype-phenotype correlation in the disease.Results The sequencing analysis showed a heterozygous mutation c.134G>A in GJB3gene in the proband and his mother. This mutation resulted in change of neutral glycine(GGG) residue at codon45to the highly charged glutamic acid (GAG), p.G45E. Thismutation was not detected in the proband’s father and676unrelated healthy controls.There is no GJB4pathogenic mutation was detected. We found that all the mutations inthe GJB3and GJB4genes kept lack of distinct correlation between genotype andphenotype in EKV.Conclusion (1) This missense mutation should be the underlying cause of moleculargenetics in erythrokeratodermia variabilis pedigree in our study. This study will lay afoundation for genetic counseling, prenatal gene diagnosis.(2) We found that all themutations in the GJB3and GJB4genes kept lack of distinct correlation betweengenotype and phenotype in EKV.