Analysis Of DSRAD Gene Mutation In A Family With Dyschromatosis Symmetrica Hereditaria

Background:Dyschromatosis symmetric hereditaria(DSH MIM127400),also known as skin heterochromia,is a rare autosomal dominant hereditary disease.It is a single gene inheritance disease.It is characterized by a combination of hypopigmentation and hyperpigmentation on the extremities of the limbs,especially the hand and the dorsal side of the foot,patients also have freckle-like skin lesions on the face.These symptoms usually occur in infants or early childhood,studies have shown that about 73 percent of patients developed these symptoms before age 6.Generally,the symptoms are limited to the skin.This disease was first reported by Japan's scholar Toyama in 1910 and then officially named DSH in 1929.Most of the cases have been reported from eastern Asian countries,mostly in Japan and China.South Korea,India and the United States also have some cases.DSH's distribution is in family form,and sporadic cases also been reported.In 2003,Miyamara,Japanese,conducted a whole-genome scan of four families to determine the disease associated with mutations in ADAR1.In the same year,Chinese zhang xuejun et al.confirmed the result by scanning the whole genome of 2 families,and positioned the gene in the 9.4 cm section between 1q11-1q21.DSH's pathogenic gene ADAR1 is about 40kb and has 15 exons.The gene encodes a double-stranded RNA specific adenosine deaminase which is expressed in various tissues of the body.The structure includes the nuclear signal NES,two z-DNA binding domains(Z alpha and Z beta),three dsRNAs binding domains(DSRM1,DSRM2,DSRM3)and deaminase domain,with a total of 1226 amino acids.The DSRM(especially DSRM1,DSRM3)and deaminase domain are necessary structures for the activity of ADAR1 enzyme.ADAR1 catalyzes the transformation of adenine nucleoside into inosine nucleoside.The catalytic reaction reduces the stability of dsRNA's double-strand,replaces the amino acids in the protein translation,which means converting A to I and pairing it with G by the ribosome and polymerase,and then changes the sequence information and structure,resulting in subsequent physiological effects.Up to now,more than one hundred kinds of mutations have been reported around the world,including missense mutation,frame shift mutation,nonsense mutations and splice mutations,scattering in the all fragments of the gene,there is no obvious mutation hot spots.In this study,we detected a family,expected to find a new mutation in the ADAR1 gene and to amplify the mutation spectrum of the gene.This study may lay a solid foundation for the diagnosis of this disease,the clarification of pathogenic mechanisms and the gene therapy.Objective:To identify and analyze the mutation sites of ADAR1 gene in a Chinese family with dyschromatosis symmetrica hereditaria.The suspected members of the family were genetically diagnosed.Methods:To collect the peripheral blood of the family members,extract the DNA,and amplify all 15 gene exon of the ADAR1 gene by PCR,DNA direct sequencing was conducted,and recruit 96 normal human as control.Results:We detected a deletion mutation(c.767delA)in exon 2 of ADAR1 gene in the proband and other patients of the family,resulting in a frameshift mutation,the other two children without any symptoms also have this mutation.But this mutation was not found in other unaffected family members and the controls.Conclusion:Mutation of p.H256fs-260X in the ADAR1 gene is first reported in the DSH family,this mutation may impair ADARI protein function,and cause dyschromatosis symmetrica hereditaria.