Studies On Molecular Genetics Of Six Congenital Nystagmus Families

ObjectiveTo identify the molecular defect of six Chinese congenital nystagmus families, including four X-linked congenital idiopathic nystagmus （XL-CIN） families and two sensory defect nystagmus（SDN） families with aniridia.Methods1. XL-CIN:The members of the four pedigrees were recruited, clinical examinations were performed, and genomic DNA was extracted from peripheral blood leukocytes. The coding exons and splice junctions of the human FRMD7gene were amplified by polymerase chain reaction （PCR）. The PCR products were purified, and then were performed direct sequencing. The mutation detected was confirmed in available other family members through co-segregation analysis.2. SDN: Eleven members of the two pedigrees were recruited, clinical examinations were performed, and genomic DNA was extracted from peripheral blood leukocytes. The coding exons and splice junctions of the human PAX6gene were amplified by polymerase chain reaction （PCR）. The PCR products were purified and sequenced. When any interesting sequence variation suggestive of a mutation was found in the proband, it was later confirmed in parents and available relatives as well as in50normal unrelated individuals from the same ethnic background by directly sequencing the particular exon.Results1. The genetic models of four families with congenital idiopathic nystagmus were X-linked dominant inheritance with incomplete penetrance. FRMD7mutations were found in two of four families with XL-CIN:a missense mutation c.G886C（p.G296R） in exon8of FRMD7was detected in family XL-CIN02, and a nonsense mutation c. C910T （p.R304X） in exonlO of FRMD7gene in family XL-CIN03.2. Two sensory defect congenital nystagmus families accompanying with congenital aniridia showed autosomal dominant inheritance. The patients of SDN-01family also showed macular dysplasia and presenile cataract. A heterozygous mutation c.95₁05dup11of PAX6was found in all of two patients in family SDN-01, not in unaffected individuals. This mutation is predicted to result in the truncation of the protein product within the linker region of PAX6（p.G36X）. SDN-02pedigree were simple aniridia, a heterozygous mutation c.C607T of PAX6was found in all of four patients in family SDN-02, not in unaffected individuals. This nonsense mutation is predicted to result in the truncation of the protein product within the linker region of PAX6（p.R203X）.The mutations co-segregated with the disease phenotype in all available family members.Conclusion1. Two known FRMD7G296R and R304X mutations were identified in Chinese XL-CIN family XL-CIN02and XL-CIN03, respectively.2. A de novo mutation of the PAX6gene （c.95₁05dup11） was reported firstly in family SDN-01associated with aniridia, macular hypoplasia and presenile cataracts.3. The known mutation R203X, one of the three common recurrent mutations in PAX6, was also presented in Chinese sensory defect nystagmus family（SDN-02） with simple aniridia.