Genetic Analysis On Pedigree Of Congenital Albinism Type 1

Genetic polymorphism is basis of phenotypic diversity,part of them can alsocause genetic disease.Genetic mutation results in important functional change could lead to genetic disease in a family.Disease caused by pathogenic gene inherited from the parent or changes in genetic material affected by external physical and chemical factors are called genetic disease.In this study,a large congenital ocular albinism type 1 pedigree from Yunnan,China was analyzed,with a total of 113 members within six generations.Several cases with genetic disease were found in this pedigree.The pathogenic phenotype of patients was nystagmus and decreased pigmentation in the fundus,which was a typical model of genetic disease in pedigree.Through high-throughput sequencing technology,whole-genome sequence alignment and Perl scripting are used to screen for mutations.Whole-genome of patients and carriers in this family was systematically analyzed to detdct functional variations that determine ocular albinism.By genomic comparing of patients,carriers and healthy people,and the Sanger sequencing verification,all patients and carriers were observed to have a deleterious mutation that can result in functional deletion of gene GPR143.This mutation was a DNA deletion of 74 bp located in the first exon of GPR143,but the deletion was not found in unaffected family members.Functional analysis showed that the deletion resuled in a stop codon,and the gene GPR143 was unable to translate the normally functioning protein.The normal gene GPR143 encodes a protein with 404 amino acids,while the mutant gene GPR143 encodes only 74 amino acids.GPR143 is a key gene in the process of eyeball development and fundus pigmentation,the encoded protein targets melanosomes in pigment cells and participates in intracellular signal transduction.Loss of function would cause abnormalities in eye development and pigmentation in the fundus,and many studies had suggested that the deleterious mutations of gene GPR143 were the cause of ocular albinism.In this study,whole-genome data of this disease pedigree was obtained by highthroughput sequencing technology,abnormal mutations of candidate sample were detected by genome-wide sequence alignment.Perl scripts were used to screen the mutations based on Mendel inheritance model,and pathogenic variations in this pedigree were determined by functional analysis.The candidate mutation sites were sequenced to verify in whole pedigree members.Based on analysis of genotype with phenotype,the 74 bp deletion of GPR143 was found to be completely consistent with pathogenetic and affected individuals.Combining all evidences,it could be confirmed that the74 bp fragment deletion located on gene GPR143 is the direct cause of genetic disease in this pedigree.Conclusion: in the observed pedigree of congenital albinism,the variant found in gene GPR143 resulted in ocular albinism,accompanied by nystagmus and causing severe visual impairment in the affected individuals.This functional variation was the first time discovered in ocular albinism patients.Results not only enriched the mutation spectrum of gene GPR143,but also revealed the important role of gene GPR143 in eyeball development and fundus pigmentation.This genetic data is important to provide for the future functional studies,clinical diagnosis,differential diagnosis and genetic counseling.