Mapping And Identification Of The Disease Gene For Four Congenital Nystagmus Families

Backgrounds: Congenital nystagmus (CN) is a common oculomotordisorder characterized by binocular spontaneous oscillations, with onsettypically at birth or within the first few months of life. The disease isregarded as idiopathic, after exclusion of nervous and ocular disease. Themechanism for this disease is unknown, and the genetic model is various.Recently, gene mutation of the FRMD7 gene at Xq26.2 was identified forcongenital nystagmus. We collected four families with congenitalnystagmus. The responsible locus of familyl was mapped to Xq26-27 in2004. Family2 and family3 are X-linked congenital nystagmus familiesand can be applyzed by linkage analysis. In family4, the affectedindividuals are all found in same generation and the gentic model isunknown.Obeetives: To identify the disease gene linked locus of family2 andfamily3 and to find out the causative gene for four congenital nystagmusfamilies.Methods and results: Different stratedge were performedaccording to the information of every family. Firstly, linkage analysis wascarried out in family2 and family3, two-point lod score was calculatedusing the M-link program of the LINKAGE sorftware package, version5.1. The maximum two-point lod score 1.76 was obtained at DXS8041,DXS8033 and DXS1062 in family 2, as well as 1.16 was obtained atDXS8009, DXS8041, DXS1062 and DXS8094 in family3. Meanwhilethe haplotype analysis localised the disease gene to a region betweenmicrosatellite markers DXS1047 and DXS8049 which equaled toXq25-26.3 in chromosome X. These data provided evidence of linkagebetween this disease and FRMD7 which had been mapped within theregion. Secondly, to identify the causative gene for congenital nystagmusin these four families, we directly sequenced both of coding sequence andthe intron-extron boundaries of the FRMD7 gene. One novel missencemutation c.781C〉G which transformed 261 Arg to Gly was detected infamilyl, another novel missence mutation c.886G〉C which transformed296 Gly to Arg was detected in family2, and a nonsence mutationc. 1003C〉T which had been reported before was detected in family3, this mutation transformed the 335 Arg to stop code. All the mutations wereco-segregated with the disease phenotype and not found in 100 normalcontrol samples.Conclusion: FRMD7 was the causative gene for familyl, family2and family3. No mutation of FRMD7 was detected in family4, suggestingthat the mutation in non-coding sequence of FRMD7 or other unknowngene was involed in the congenital nystagmus of family4.