Localizing multiple X chromosome-linked retinitis pigmentosa loci using multilocus homogeneity tests.

Abstract

Multilocus linkage analysis of 62 family pedigrees with X chromosome-linked retinitis pigmentosa (XLRP) was undertaken to determine the presence of possible multiple disease loci and to reliably estimate their map location. Multilocus homogeneity tests furnished convincing evidence for the presence of two XLRP loci, the likelihood ratio being 6.4 x 109:1 in favor of two versus a single XLRP locus and gave accurate estimates for their map location. In 60-75% of the families, location of an XLRP gene was estimated at 1 centimorgan distal to OTC, and in 25-40% ofthe families, an XLRP locus was located halfway between DXS14 (p58-1) and DXZJ (Xcen), with an estimated recombination fraction of 25% between the two XLRP loci. There is also good evidence for a third XLRP locus, midway between DXS28 (C7) and DXS164 (pERT87), supported by a likelihood ratio of 293:1 for three versus two XLRP loci.Retinitis pigmentosa (RP) is a group of hereditary progressive disorders of the retina characterized initially by night blindness, often within the first two decades of life, reduction of peripheral or side vision, eventual decrease in central vision to variable degrees, in many cases leading to total blindness due to degeneration of the retina (1). There are several subtypes of RP, including autosomal recessive, autosomal dominant, and X chromosome-linked forms (XLRP).Linkage analyses in families with XLRP have shown conflicting results regarding the location of the disease locus. Consequently, the presence of two XLRP loci was hypothesized (2-5). One subtype of XLRP, referred to as RP2, was linked to locus DXS7 (L1.28) (6, 7); another subtype, RP3, was linked to locus OTC (ornithine carbamoyltransferase) (8-10). Further evidence for location of an XLRP locus distal to OTC came from a patient with a deletion starting between OTC and DXS84 (754) and extending toward the telomere, in whom several X-chromosome linked diseases occurred including RP (11). Friedrich et al. (12) found another locus responsible for XLRP to be closely linked to DXS7, between Xcen and DXS7 (L1.28).The current study was initiated as a collaborative effort (i) to obtain evidence for XLRP heterogeneity if at all present, and, if so, (ii) to localize the disease loci in a comprehensive linkage and heterogeneity analysis.Family Data. A total of 62 families were available for this analysis, most but not all of which have been published previously. For calculation efficiency, some pedigrees had earlier been broken down into smaller families and analyzed separately; here, they were analyzed undivided. Disease status for both affected males and carrier females was determined by the investigators and was incorporated unaltered in this analysis.In many cases, heterozygous women also have symptoms that are, however, generally much milder than in men. Where detectable, such symptoms have been used for carrier status determination.Linkage Analysis. The linkage analysis was carried out with the LINKAGE programs version 4.7 (13). Map distances between markers whos...

MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes

“…As in any polygenic disease, no single gene is sufficient or, in general, necessary to cause the disease; therefore, although linkage with the HLA region has been detected in most IgAD patients and in all instances the risk attributable to this region is roughly equal, this does not indicate that just one MHC gene is conferring susceptibility to all of them. Functionally related genes are frequently linked to each other (38) and a single linkage signal to a region of a chromosome may actually be the result of disease-predisposing alleles in different linked genes in different pedigrees, as is the case for X-linked retinitis pigmentosa, where the existence of several genetic defects in the same chromosomal region has been proven (39). The MHC (HLA region in humans) is an extended cluster of genes that are remarkable for the number and importance of the immunological functions they encode (40,41), and already, in some other immune-mediated diseases, more than one MHC gene has been primarily involved (42)(43)(44)(45).…”

Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

“…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]. On the basis of linkage analyses, the frequency of RP3 as a fraction of XLRP is 56 to 90%, and RP2 accounts for most of the remainder Ott et al, 1990;Teague et al, 1994;Bergen et al, 1995;Fujita et al, 1997].…”

“…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]. On the basis of linkage analyses, the frequency of RP3 as a fraction of XLRP is 56 to 90%, and RP2 accounts for most of the remainder Ott et al, 1990;Teague et al, 1994;Bergen et al, 1995;Fujita et al, 1997]. Cloning of RP2 in Xp11.23 [Schwahn et al, 1998] (MIM# 312600) and subsequent mutation analysis have confirmed that RP2 accounts for 10 to 25% of XLRP.…”

The human retinitis pigmentosa GTPase regulator gene variant database

“…XLRP has been genetically mapped to at least five loci: RP2, RP3, RP23, RP24, and RP34 [Meindl et al, 1996;Gieser et al, 1998;Schwahn et al, 1998;Hardcastle et al, 2000;Melamud et al, 2006]. RP3 is predicted to account for 70 to 90% of XLRP cases [Ott et al, 1990;Teague et al, 1994], the RP GTPase regulator (RPGR) gene (MIM] 312610) accounts for the RP3 locus and is mutated in up to 20% of all RP patients [Breuer et al, 2002].…”