A Family With Congenital X–Linked Inherited Nystagmus and Mutation in CDR1

Abstract

Abstract: : Purpose: To identify the gene responsible for X–linked congenital nystagmus Methods:A 6–generation family with x–linked congenital nystagmus was evaluated. Complete ophthalmic examination was performed including best corrected visual acuity, slitlamp and fundus examination. Blood was collected after informed consent from all family members and linkage analysis was performed using the ABI prism linkage mapping set MD10 for the X chromosome. Lod scores were calculated with MLINK using equal allele frequency, a new mutation rate of 0.0001 and a penetrance of 95%. Candidate genes located in the linked region were evaluated by direct sequencing of each exon. The mutation observed in CDR1 was checked in 358 chromosomes. Results: Transmission was typical of Y–linked inheritance with women less severely affected and reduced penetrance (70%). Linkage analysis revealed lod scores of 3.68 for DXS1192, 2.19 for DXS1192 and 3.22 for DXS8043. These markers define a region of 55 cM in which the candidate gene CDR1 was located. Sequencing of this candidate gene revealed a c19G/A transition at position 19 of the cDNA (the A of the initiation codon being +1), modifying the Val codon at position 7 to methionine (Val7Met). This base change was never observed in 358 X chromosomes from controls of the same ethnic origin. Conclusions: We confirmed the presence of a locus for congenital nystagmus in the distal long arm of chromosome X, encompassing DXS1192 and DXS8043 and observed a mutation in the CDR1 gene. Although the physiological role of CDR1 is still unknown, it encodes a protein that is expressed in patients with paraneoplasic cerebellar degeneration. Such patients exhibit strong nystagmus. In there initial mapping report, Kerrisson et al. excluded mutations in the CDR1 (1999) as the cause of NYS1. Molecular investigation in additional families will show whether this base change represents a rare polymorphism or a true mutation.

Keywords: nystagmus • gene mapping • linkage analysis