Characterisation of a highly polymorphic microsatellite at the DXS207 locus: confirmation of very close linkage to the retinoschisis disease gene.

Abstract

Juvenile retinoschisis (RS) is an X linked recessive vitreoretinal disorder for which the basic molecular defect is unknown. The gene for RS has been previously localised by linkage analysis to Xp22.1-p22.2 and the locus order Xpter-DXS16-(DXS43, DXS207)-RS-DXS274-DXS41-Xcen established. To improve the resolution of the genetic map in the RS region, we have isolated a highly polymorphic microsatellite at DXS207, which displays at least nine alleles with a heterozygosity of 0-83. Using this microsatellite and four other Xp22.1-p22.2 marker loci, DXS16, DXS43, DXS274, and DXS41, we performed pairwise and multilocus linkage analysis in 14 kindreds with RS. The microsatellite was also typed in the CEPH (Centre d'Etude du Polymorphisme Humain) reference families. Tight linkage was found between RS and DXS207 (Z(O) = 14-32 at 0 = 0O0), RS and DXS43 (Z(0)=8-10 at 0=00), and DXS207 and DXS43 (Z(0) = 4031 at 0 = 00). Our linkage results combined with data previously reported suggest that the DXS207-DXS43 cluster is located less than 2 cM telomeric to the RS locus. The microsatellite reported here will be a very useful marker for further linkage studies with retinoschisis as well as with other diseases in this region of the X chromosome.(J Med Genet 1993;30:300-3) Despite the variability in the clinical expression of the disease, no evidence for genetic heterogeneity for RS was found. These results have already rendered genetic prediction feasible in many RS families.2 A more precise mapping of the RS locus is a prerequisite for positional cloning. Accuracy of genetic mapping, including identification of recombinants which provide crucial information for orienting the gene search, was limited by the lack of highly informative markers in the region of the RS gene. We have identified a highly informative microsatellite marker at DXS207. Our linkage results suggest that this marker is located less than 2 cM telomeric to the RS locus. Patients and methods PATIENTSFourteen unrelated families with X linked recessive retinoschisis were analysed, seven of which have been used in a previous linkage study reported by Kaplan et al.2 The diagnosis was, in each case, confirmed by careful ophthalmological examination. DNA analysis was performed on 181 subjects including 39 affected males.

Loss of heterozygosity at chromosome segment Xq25-26.1 in advanced human ovarian carcinomas

“…Each of the matched pairs of normal and tumor DNAs were subjected to PCR analysis with 26 microsatellite markers on the X chromosome: DXS987, DXS996, DXS 999 (Weissenbach et al, 1992), DXS 237 (Gedeon et al, 1992), KAL (Bouloux et al, 1991), DXS 207 (Oudet et al, 1993), DXS 989, DXS1047, DXS1053, DXS1062, DXS1193, DXS1195, DXS1206, DXS1226, DXS1227, DXS1229, (Gyapay et al, 1994, DXS6680, DXS6679 (Carvalho et al, 1994), DMD (Clemens et al, 1991), DXS228, PFC (Coleman et al, 1991), DXS7 (Moore et al, 1992), MAOA (Hinds et al, 1992), HPRT, ARA (Edwards et al, 1992), and DXS458 (Weber et al, 1990). All of the markers except HPRT (tetranucleotide repeats) and AR (tri-nucleotide repeats) contain dinucleotide repeats.…”

Expressed sequence tags (ESTs)

“…Similarly, DRES10 was mapped to Xp22 (Fig. 2d), the region known to harbor the locus for X-linked juvenile retinoschisis (49). Based on the sequence homology and mapping assignment, both these human cDNAs could be considered very strong candidates for human retinopathies (see below).…”

Regional localisation of a non‐specific X‐linked mental retardation gene (MRX19) to Xp22

“…The position of KAL was estimated from data of Zhang et al [19931. The approximate 90% support interval for the localisation was determined using the lod-1 method [Conneally et al, 19851 applied to the multipoint lod score. Although the lod-1 method is now standard for the estimation of confidence intervals from Oudet et al, 1992Weissenbach et al, 1992Browne et al, 1992Weissenbach et al, 1992Browne et al, 1992Weissenbach et al, 1992Oudet et al, 1990Feener et al, 1991Weissenbach et al, 1992Coleman et al, 1991Donnelly et al, 1994Donnelly et al, 1994Weber et al, 1990Donnelly et al, 1994Luty et al, 1990Edwards et al, 1991Gedeon et al, 1992Weissenbach et al, 1992Richards et at., 1991 two-point lod scores, it was not designed for application to multipoint lod scores [Keats et al, 19891. The exact significance level associated with the lad-1 method is unclear, especially where multipoint lod scores are multimodal.…”