Study On The Mutations Of ATP2C1 Gene In Chinese Patients With Hailey-Hailey Disease

Background Hailey–Hailey disease (HHD; MIM 16960), or familial benign chronic pemphigus, is a rare autosomal dominant inherited disorder initially described by Howard and Hugh Hailey in 1939. It is characterized by recurrent pruritic vesicles and erosions, particularly involving the body folds such as the axillae, groin and neck. Histology revealed suprabasal cleavage in epidermal cells of the spinous layer, with loss of intercellular bridges. Ultrastructural studies have revealed the breakdown of desmosome keratin filament complexes with a perinuclear aggregation of keratin intermediate filaments that have retracted from desmosomal plaques.Linkage analysis mapped the HHD locus to chromosome 3q21–q24. Recent studies have revealed that HHD is caused by heterozygous mutations in the ATP2C1 gene, which encodes the human secretory pathway Ca2+/Mn2+-ATPase protein 1 (hSPCA1). A spectrum of missense, frameshift, splice-site, and nonsense mutations have since been reported in ATP2C1 gene. Comparison between genotype and phenotype failed to yield any clear correlation between the nature of the mutation and the clinical features of HHD. In the present study, we have ascertained four familial and two sporadic cases with HHD, and examined ATP2C1 gene mutations in these families by direct sequencing.Objectives To identify pathogenic mutations of the ATP2C1 gene in four familial and two sporadic cases of HHD.Methods We collected four familial and two sporadic cases of HHD and their blood samples. Genomic DNA was extracted from peripheral blood.All the coding exons and their flanking sequences of ATP2C1 were amplified by polymerase chain reaction and products analyzed by direct sequencing. Results We present four novel, distinct, heterozygous mutations in Chinese HHD patients, two splicing mutations ((235-2 A→G,117+2 T→G) in one family and one sporadic case, one nonsense mutation (W285X) and one missense mutation (G530R) respectively dominantly inherited in the patients of two families. However, no mutations were found in another family and one sporadic patient. These four mutations were not found in the healthy members of families or sporadic cases and in 100 unrelated control individuals.Conclusions Our data suggests that these four novel mutations in the ATP2C1 gene could cause HHD in Chinese Han population and provide more molecular evidences for ATP2C1 mutational events in the pathogenesis of HHD.