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Congenital nystagmus (CN) is a hereditary disease characterized by bilateral ocular oscillations that occur within the first 6 months of life.[1] Congenital motor nystagmus (CMN) is a subtype of CN that is usually diagnosed after sensory defect nystagmus has been ruled out.[2] Although several inheritance patterns for CMN have been proposed, no causative gene has been identified in most of the reported linkage loci. In this study, two families with CMN (nys-01, nys-02) were investigated for four generations. Family nys-01 included 15 individuals with CMN, 22 normal individuals and 15 spouses, while family nys-02 included nine individuals with CMN, nine normal individuals and eight spouses. This study was approved by the Ethics committee of Nanhua University. The criteria used in this study to diagnose CMN were reported previously.[3]

Genome-wide screening was conducted with 382 markers in 10-cM intervals. Fine mapping was accomplished using fluorescent-labelled primers designed from the Decode linkage map. Alleles were analysed by GENESCAN Analysis (version 3.7, Applied Biosystems, Foster City, CA, USA) and GENOTYPER (version 3.7, Applied Biosystems) software. Two-point logarithm of odds (LOD) score was calculated by the MLINK program of the LINKAGE package (version 5.1, Applied Biosystems). We assumed that the disease is an X-linked trait with 99% penetrance. Marker allele frequency was set at 1/n, where n is the number of alleles observed. We assumed gene frequencies of 0.0001 and no sexual difference in recombination rate. Multipoint linkage analysis was used to estimate the optimal position. For multipoint linkage calculation, the genetic distance between loci was calculated using Gene Browser (http://www.genome.ucsc.edu). The haplotype was constructed using the Cyrillic program to define the borders of the co-segregating region.

All CMN patients had vision loss (0.2–1.2) with no other oculopathy present. Family inheritance analysis indicated that the disease gene of CMN is located on the X chromosome, and its inheritance mode is X-linked dominant inheritance with incomplete penetrance. Sixty-nine members of the two families were genotyped. Linkage study was performed using 16 microsatellite markers at about 10-cM intervals on the X chromosome. Among the 16 microsatellite markers, DX1047 yielded significantly positive LOD scores (LOD > 2, and sita = 0) in both families. Linkage study was further performed using 20 microsatellite markers around DXS1047. In the nys-01 family, some microsatellite markers, such as DX8059 and DX8071, revealed high LOD scores (Table 1). DXS1047 and DXS1205 exhibited high LOD scores in the nys-02 family (Table 1).

Table 1. Two-point LOD score with polymorphic DNA markers on the X chromosome
OrderPositionLOD score at Ɵ =ZmaxƟmax
  0.00.10.20.30.4  
  1. LOD, logarithm of odds.

Family nys-01        
DXS8055114.5−0.442.722.381.690.842.720.1
DXS8053115.42.853.903.142.141.003.900.1
DXS1001119.65.556.225.033.501.686.220.1
DXS8059122.02.591.761.681.290.722.590.0
DXS8078126.33.773.152.451.670.843.770.0
DXS1047128.88.557.175.633.871.868.550.0
DXS8071131.23.653.042.371.610.813.650.0
DXS8041133.41.116.425.173.591.736.420.1
DXS8074133.83.723.012.251.460.673.720.0
DXS8033133.9−3.664.003.162.090.934.000.1
DXS8094136.0−3.856.475.233.641.766.470.1
DXS1041136.3−6.444.213.362.251.024.210.1
DXS1211138.0−6.733.973.172.110.953.970.1
Family nys-02        
DXS8059121.9−4.11−0.120.220.290.200.290.3
DXS8098122.6−3.690.810.850.580.220.580.2
DXS8057123.3−9.790.410.750.650.330.750.2
DXS8009125.8−3.072.031.671.100.442.030.1
DXS8044126.3−4.890.320.420.360.220.420.2
DXS1047128.83.613.022.351.600.783.610.0
DXS1041136.21.811.491.130.730.311.810.0
DXS1211138.03.913.272.561.750.863.910.0
DXS1205139.93.913.272.561.750.863.910.0
DXS1227140.5−3.991.341.230.950.541.340.0

Haplotype analysis of the nys-01 family showed that there were special haplotypes between DXS8055 and DXS1211 in all affected members and carriers. Recombination occurred in three individuals. Therefore, we proposed a locus for CMN between DXS1001 and DXS8041 with a 13-cM interval in the nys-01 family. Haplotypes were also analysed in the nys-02 family. Recombination was found in two members. Multipoint linkage analysis in these two families demonstrated that a disease gene may be located between DXS8044 and DXS1227 (Fig. 1). The genotypes of nys-01 and nys-02 suggested that the disease gene of CMN may be located between DXS8041 and DXS8044 on Xq25-26.3 with a 7.1-cM interval. We therefore located the causative genes of CMN to a 7.1-cM interval between Xq25 and Xq26.3, and proposed that there are two independent CMN causative genes.

figure

Figure 1. Multipoint logarithm of odds (LOD) score. (a) LOD with support interval localizes the gene in a region between DXS1001 and DXS8041 in family nys-01. The markers and intervals: DXS8055-0.9 cM-DXS8053-4.2 cM-DXS1001-2.3 cM-DXS8059-4.2 cM-DXS8078-2.53 cM-DXS1047-2.3 cM-DX8071-2.26 cM-DXS8041-0.38 cM-DXS8074-0.1 cM-DXS8033-2.1 cM-DXS8094-0.03 cM-DXS1041-1.77 cM-DXS1211. (b) LOD with support interval localizes the gene in a region between DXS8044 and DXS1227 in the nys-02 family. The markers and intervals: DXS8059-0.65 cM-DXS8098-0.66 cM-DXS8057-2.6 cM-DXS8009-0.43 cM-DXS8044-2.47 cM-DXS1047-7.46 cM-DXS1041-1.76 cM-DXS1211-1.95 cM-DXS1205-0.54 cM-DXS1227. (c) Xq-linked nystagmus with different inheritance patterns. Series A shows the X-linked dominant pattern with incomplete penetrance (A1, assigned by Kerrison et al.[5]; A2 and A3 refined in the nys-01 and nys-02 families, respectively). B shows the X-linked dominant pattern with 100% penetrance. C shows the X-linked recessive pattern.

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In this study, the causative disease genes of CMN in two Chinese CMN families were mapped to a locus on chromosome Xq25-q26.3 through exclusion of other regions in the X chromosome by LOD scores of minus infinity, LOD scores higher than 2 for several makers in this locus, and haplotype analysis. Our study indicated that the most common mode of inheritance for CMN is X-linked dominant with incomplete penetrance.

In 1999, Kerrison and colleagues investigated the linkage region of CMN in three families and demonstrated an X-linked, irregularly dominant inheritance of CMN. The disease gene was located on the NYS1 gene between GATA172DO5 and DXS1192 on Xq26-q27.[3] In a later study, this gene was found to be located on a 15.8-cM interval between ATA59C05 and DXS1192.[4] In 2011, the same group narrowed the CMN locus to a region between ATA9909 and DXS1211.[5] Recently, three other loci for X-linked CMN, such as Xq23-q27, Xp11.4–11.3 and Xp22.3, have been proposed.[6, 7] Among these four loci, Xq23-q27 and Xp22.3 were previously indentified in Chinese CMN families. An autosomal dominant CMN was also mapped to 1q31-q32.2 in Chinese populations.[6] In this study, we described two large Chinese families with X-linked dominant CMN and mapped the disease genes to Xq25-q26.3. However, our locus overlaps partially with the region reported by Kerrison et al.[3] The non-overlapping region may suggest a possible location for new disease genes. Mutation of genes in the regions identified by previous studies was thought to be a main factor for CMN.[8] However, causative mutation was not commonly identified in previously reported linkage regions.[6, 7] Our study provides no evidence for mutation of genes in the linkage region. However, studies on other Chinese CMN families localized the disease to different chromosomes or at different loci on the X chromosome, suggesting that: (i) multiple disease genes may be responsible for CMN; (ii) other transmissible gene-silencing mechanisms may play a role in CMN besides gene mutation; and (3) the disease gene may not be population-specific.

Our study further suggested that CMN may be a group of heterogenous disorders, and multiple disease genes are responsible for causing CMN. Linkage analysis provides a platform for further identification of disease genes. However, some attention should be paid to the transmissible gene silencing mechanism because gene mutation was not commonly found in these reported linkage regions.

References

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    Zhang B, Liu Z, Zhao G et al. Novel mutations of the FRMD7 gene in X-linked congenital motor nystagmus. Mol Vis 2007; 13: 16741679.