Detection Of ATP2C1 Mutation In A Family With Hailey-Hailey Disease

Background Benign familial chronic pemphigus,or Hailey-Hailey Disease (HHD;OMIM 169600),is a rare autosomal dominant inherited disorder of bullous skin diseases.It was first described by the Halley brothers in 1939.The males and females are equally affected by HHD,which has family history in 70%of patients with the disease.It is characterized by recurrent pruritic blisters and erosions,involving intertrigmous areas such as the neck,armpits,groin,and perineum.Histopathology, HHD is characterized by loss of cohesion between keratinocytes(acantholysis) with epidermal cleft or vesiculation.Widespread partial loss of intercellular bridges between keratinocytes gives the epidermis the appearance of a dilapidated brick wall.Recent studies have revealed HHD was caused by heterozygous mutations in the ATP2C1 gone,which located on chromosome 3q21-24.A spectrum of missense,splice site,nonsense,and frameshift mutations have been reported in ATP2C1 gone.Most of gone mutations have lead to premature termination codon.ATP2C1 gone mutations lead to calcium ions regulation obstacles in keratinocytes intracellular,and calcium ions plays an important role on the keratinocytes intercellular adhesion,and calcium ions signaling obstacles lead to acantholysis of epidermal layer,which results in unique pathological change.Although most researches on ATP2C1 gone mutations were carried out at home and abroad,genotype/phenotype correlations are still unknown.Objective To identify ATP2C1 gone mutation in a Chinese family with HHD.To analyze the clinical features and the ATP2C1 gone mutations of all HHD reported in China and explore the correlation between the genotypes and phenotypes.This study will provide a scientific basis for the genetic diagnosis and genetic counseling. Methods We collected one Chinese HHD family and 100 unrelated healthy controls and their blood samples.Genomic DNA was extracted from peripheral blood.All the coding exons and their flanking sequences of ATP2C1 gene were amplified by polymerase chain reaction and products analyzed by direct sequencing.All articles about gene mutations of HHD were searched by Chinese Biology Medicine(CBM) and www.ncbi.nlm.nih.gov,and the clinical features of HHD and the gene mutations were summarized and analyzed.Results 4 patients with HHD in this family showed a heterozygotic mutation at nucleotide.457(C＞T),resulting in the substitution of premature termination codon (PTC) for arginine at codon 153.Meanwhile the mutation was not found in all controls, which proved that this mutation was the pathogenic mutation of this HHD family.A large number of ATP2C1 mutations reported to date lead to PTC,which is approximately 54%(19/35) of the total.Conclusions The nonsense mutation c.457C＞T of ATP2C1 gene may be underlying causes of HHD in this Chinese family rather than single nucleotide polymorphism (SNP).This study should be useful for genetic counseling,prenatal diagnosis and gene therapy for the patients and explore the correlation between the genotypes and phenotypes.