Mapping And Identification Of The Responsible Gene For X-linked Idiopathic Congenital Nystagmus (XLICN) In Chinese Families

Congenital nystagmus(CN) is a common oculomotor disorder(frequency of 1/1,500 live births) characterized by bilateral involuntary,periodic,predominantly ocular oscillations.CN onset typically occurs at birth or within the first few months of life and occurs secondary to the genetic ocular diseases such as albinism,achromatopsia,and Leber congenital amaurosis(OMIN 204000).CN can be an idiopathic disease or associated with various diseases as a syndrome. The inheritance model is mainly X-linked idiopathic congenital nystagmus(XLICN),but autosomal recessive(OMIN 257400) and autosomal dominant(OMIN 164100,608345,193003) forms have been described.Some studies indicated that two disease loci of XLICN were mapped to Xq26-q27 and Xp11.4- Xp11.3.Recently, Tarpey et al.identified several mutations in FRMD7(OMIN 300628),a gene localizing to Xq26-q27 and responsible for a major part of XLICN.To identify the responsible gene for X-linked idiopathic congenital nystagmus (XLICN),the members of six XLICN families were recruited and were genotyped with microsatellite markers around the FRMD7 locus.Mutations were comprehensively screened by direct sequencing using gene specific primers.An X-inactivation pattern was investigated by X chromosome methylation analysis for different penetrance analysis. We found two different novel mutations of FRMD7 gene in two different XLICN families and found one SNP of FRMD7 gene.We analysis the X chromosome inactivation in the Shangdong family.We found the first mutation is a missense mutation of FRMD7 gene from Shangdong province XLICN family.The mutation is a transversion(c.812G＞T) in exon 9, which caused a conservative substitution of Cys to Phe at codon 271(p.C271F).This mutation cosegregated with all affected individuals and was present in the obligate, non-penetrant female carriers.However,the mutation was not observed in unaffected familial males or 400 control males.The locus of mutation located in conservated region of FRMD7gene.The second mutation in FRMD7 gene is a frame-shift mutation from Nanjing province XLICN family.The locus of mutation is c.1274-1275delTG(p.Glu426AlafsX4), which caused a frameshifi from codon 426 and subsequent premature truncation of the FRMD7 protein just two amino acids downstream(p.428X).Although this mutation is not in conservated region of FRMD7 gene,truncating mutations usually affect the stability of the mRNA.mRNA containing the mutation is highly unstable,and can be degraded by nonsense-mediated mRNA decay(NMD),the cartier would have nystagmus.In addition,we found one SNP in FRMD7 gene in other XLICN families.The SNP is a transversion(c.656G＞T) in exon 7.The result of X-inactivation analysis in Shangdong XLICN family indicated skewed X-inactivation is not the reason of the incomplete penetrance of female carriers in this family.Maybe there are other factors associated with this phenomenon.In conclusion,we have identified two novel mutations in FRMD7 gene for XLICN. And this finding will widen the mutation spectrum of the FRMD7 gene and confirm that FRMD7 plays an important role in motor control of eye movement.These findings also showed that mutation analysis of FRMD7 has a diagnostic value in Chinese XLICN families.