Mapping X-linked ophthalmic diseases: II. Linkage relationship of X-linked retinitis pigmentosa to X chromosomal short arm markers

Abstract

X-linked retinitis pigmentosa (XLRP) is a series of hereditary dystrophic diseases of the retina that occur in three clinically distinguishable variants: the classic form (McK31360), a type known as choroidoretinal dystrophy (McK30330), and a variant with golden-metallic or "tapetal" reflex in the heterozygote (McK30320). Controversy exists as to whether these phenotypic differences are due to clinical variability in disease expression, heterogeneity in disease alleles at a single locus, or a multiplicity of loci for XLRP. We have studied a single large kindred segregating for XLRP with the metallic fundus reflex in the heterozygote with restriction fragment length polymorphisms (RFLPs) from the short arm of the human X chromosome, and found measurable linkage to DXS7 (theta = 12.5 cMorgans at LOD = 2.5), the same RFLP previously shown by others to be tightly linked to the other forms of XLRP at theta = 3 cM. Although these estimates appeared to be different, each fell just within the 95% probability interval of the other and, therefore, were insufficient to prove or disprove that the metallic sheen form of XLRP is allelic with other forms of XLRP. Additional RFLPs at the DXS43 and the ornithine transcarbamoylase loci provided three-point crosses for determining the relative positions of DXS7 and XLRP, and supported an order that placed this form of XLRP distal to DXS7 on the Xp. Until the question of genetic heterogeneity is resolved, careful phenotypic characterization of the clinical type of XLRP present in families being used for linkage analyses is advisable.

Report of the committee on the genetic constitution of the X and Y chromosomes

“…31260, 30330 and 30320) and autosomal forms. The initial report of Bhattacharya et al (1984;1985) for the linkage between RP2 and DXS7 has been confirmed by many groups (Clayton et al 1986;Nussbaum et al 1985a;Mukai et al 1985;Friedrich et al 1985; Francke et al (1985) who possessed a deletion of Xp21 with DMD, MacLeod phenotype and retinitis pigmentosa may not have had X-linked RP (see discussion of Clayton et al 1986). Alternatively, the locus deleted in this patient is the locus showing close linkage to DXS84 and OTC.…”

Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

“…A milder phenotype is often present in female carriers, probably due to random X-inactivation. Close linkage of XLRP to markers DXS7 [Bhattacharya et al, 1984;Nussbaum et al, 1985] and OTC [Musarella et al, 1988;Chen et al, 1988;Denton et al, 1988;Wirth et al, 1988;Musarella et al, 1989] was found. Subsequent linkage analysis provided evidence for two different loci: RP2 (MIM# 312600) was positioned centromeric of DXS7, while RP3 (MIM# 312610) was telomeric of DXS7 and mapped between DXS1110 and OTC [Musarella et al, 1988;Chen et al, 1989;Musarella et al, 1990;Ott et al, 1990;Dahl et al, 1991].…”

Isolation of a candidate gene for choroideremia.

“…A similar approach to choroideremia was feasible because the locus for choroideremia has been mapped to Xq2l.1-Xq2l.2 by tight linkage to polymorphic DNA markers (11)(12)(13)(14)(15)(16), by the study of individuals with choroideremia who have large deletions of this region (17)(18)(19)(20)(21)(22)(23), and by the characterization oftwo women with choroideremia and de novo X;autosomal translocations (24)(25)(26). Recently, Cremers et al (27) isolated a candidate cDNA for the choroideremia gene that was disrupted in males with the disease by large [>40-kilobase (kb)] genomic deletions and in a female with the disease by an X;13 translocation.…”