GENOMICS 8, ‘727-731 (1990)

SHORT COMMUNICATION

Localization of the Gene for Interphotoreceptor Retinoid-Binding Protein to Mouse Chromosome 14 near A/p-l

MICHAEL DANcIGER, **t CHRISTINE A. KOZAK, $ JOHN NICKERSON, 5 T. MICHAEL REDMOND,~ AND DEBORA B. FARBER**’

*Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, California; tLoyola Marymount University, Los Angeles, California;

*National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; and §National Eye Institute, Bethesda, Maryland

Received April 30, 1990; revised July 6, 1990

Interphotoreceptor retinoid-binding protein (IRBP) is a large glycoprotein known to bind retinoids and found pri- marily in the interphotoreceptor matrix of the retina be- tween the retinal pigment epithelium and the photorecep- tor cells. It is thought to transport retinoids between the retinal pigment epithelium and the photoreceptors, a criti- cal role in the visual process. We have used a 900-bp bovine IRBP cDNA fragment to map the corresponding gene, Rbp- 3, to mouse chromosome 14 with somatic cell hybrids and have positioned the gene near Npl (nucleoside phosphory- lase-1) by analysis of the progeny of an intersubspecific backcross. In the human genome, NP maps to human chro- mosome 14 and RBP3 to human chromosome 10. Thus, these two genes span the putative site of a chromosomal translocation which contributed to divergent karyotype evolution of man and mouse. 0 isso Aoademic PMU, IIN.

Interphotoreceptor retinoid-binding protein (IRBP) is a large glycoprotein synthesized by photo- receptor cells of the retina (Fong et al., 1984; van Veen et al., 1986). Human IRBP consists of 1225 amino acids (Si et al., 1989) and it is slightly smaller than bovine IRBP, which has 1264 amino acids (Borst et al., 1989). IRBP is found primarily in the interphoto- receptor matrix between the retinal pigment epithe- lium and the photoreceptors (Bunt-Milam and Saari, 1983; Rodrigues et al, 1986). It binds retinoids in a light-dependent manner (Wiggert et al., 1977; Lai et al., 1982; Liou et al., 1982; Adler et al., 1982) and has been postulated to carry out the function of transport-

’ To whom reprint requests should be addressed at the Jules Stein Eye Institute, B-237, UCLA School of Medicine, Los An- geles, CA 90024-1771.

ing retinoids between the photoreceptors and the reti- nal pigment epithelium (Chader et al., 1983). This transport function is critical to the process of photo- transduction (the light response) in the retinal pho- toreceptor cells. IRBP has also been shown to induce experimental autoimmune uveitis (EAU) in animals (Gery et al., 1986; Hirose et al., 1986) and may be in- volved in human uveitic conditions as well (Matsuo et al., 1986).

We decided to map the gene for IRBP (Rbp-3) in the mouse primarily because of our on-going interest in the genetic basis of the light response of the retina. We also wanted to determine on the basis of its molec- ular genetics if Rbp-3 is related to any of the inherited photoreceptor (or photoreceptor-involved) diseases in mice [Green (1989) has compiled a comprehensive catalog of these mutants and their (available) chro- mosome locations].

Chinese hamster and mouse DNAs were analyzed by Southern blot hybridization for sequences homolo- gous to a bovine IRBP cDNA probe (IRBP-900). IRBP-900 is an SSS-bp SaZI fragment from pIRBPlO- 1800, a plasmid that contains a 1.8-kb insert of bovine IRBP cDNA (Redmond et al., 1989). This cDNA frag- ment corresponds to a protein-encoding region in the 5.95kb exon sequence of the bovine RBP3 gene span- ning bases 2457 to 3354. Hamster DNA produced 8.6- and 5.1-kb EcoRI bands cross-reactive with IRBP- 900; the mouse produced 18.0- and 4.8-kb bands (Fig. 1, lanes 1 and 2).

A panel of 24 Chinese hamster-mouse somatic cell hybrids was typed for the mouse fragments. Four of the 24 hybrids tested contained both mouse bands, and 20’lacked both bands (Fig. 1, lanes 3-7). The chromosome content of 13 hybrids was determined by

727 o&N-7543/90 $3.00 Copyright 0 1990 by Academic Press, Inc.

All rights of reproduction in any form reserved.

728 SHORT COMMUNICATION

1 2 3 4 5 6 7

Ilkb-

FIG. 1. Autoradiogram of a Southern blot of hamster-mouse somatic cell hybrid DNAs digested with EcoRI and hybridized with the IRBP-900 cDNA probe; each lane has 6 pg of DNA. Lane 1, Chinese hamster DNA, lane 2, NFS/N mouse liver DNA; lanes 3-7, representative somatic cell hybrid DNAs. The two arrows point to the l&O- and 4.6kb mouse bands used to score for the presence of IRBP sequences in the hybrids. The numbers on the left (in kb) mark the positions of h DNA fragments produced by digestion with HindIII. The hybrids were derived from the fusion of E36 Chinese hamster cells with mouse peritoneal or spleen cells. After digestion, DNAs were electrophoresed in 1.2% agarose gels and transferred to nylon membranes by the technique of Southern (37). Hybridization was carried out as described previously (11). Labeling of the probe was done with [ol-a’P]dCTP (3000 Ci/mmol) by the random priming method (14).

trypsin-Giemsa banding followed by staining with Hoechst 33258; the remainder were typed for specific marker loci (Kozak et al, 1977; Hoggan et aZ., 1988). Correlation with the chromosome content of these hybrids showed at least three discordancies for the presence of IRBP DNA sequences on every mouse chromosome except chromosome 14 (Table 1). A sin- gle hybrid was discordant for chromosome 14 (the chromosome was present, but there were no mouse fragments that hybridized with the IRB‘P probe). Since this hybrid had not been karyotyped, it is possi- ble that it contains a deletion including the IRBP se- quences. These data indicate that the mouse IRBP gene, which we designate Rbp-3 (after the human ho- molog RBP3), probably maps to chromosome 14.

To define a more precise map location for Rbp-3, intersubspecific backcross progeny from the cross (NFS/N X Mus muscuhs muscuhs (Skive)}F, X M. m. muscuhs (Skive) were generated. Genomic DNAs

from the inbred mouse NFS/N and from the wild mouse M. m. musculus (Skive) were examined for re- striction fragment length variants with the IRBP-900 probe. For each enzyme tested the IRBP-900 probe hybridized with only one fragment from each of the two mouse DNAs. With XbaI the NFS/N DNA pro- duced an 11.4-kb cross-reactive band and with M. m. musculus a lO.l-kb band (Fig. 2). DNAs extracted from 102 backcross progeny were typed for this poly- morphism; 45 mice inherited the NFS/N fragment, consistent with the expected 1:l segregation ratio. In- heritance of the NFS/N restriction fragment was compared with segregation of alleles at two other chromosome 14 markers: Np-1 (nucleoside phosphor- ylase-1) and Es-10 (esterase-10). Mice were typed for isozymes of Es-10 and Np-1 following histochemical staining of kidney extracts on starch gels (Harris and Hopkinson, 1976). The results show close linkage be- tween Rbp-3 and Np-1 (Table 2) and suggest that the most likely map order of these three genes is centro- mere-Rbp-3-Np-I-Es-IO.

Comparative genetic mapping has suggested that mouse chromosome 14 has a region of linkage homol- ogy with human chromosome 10 (Nadeau, 1989). Thus, the genes Adk and Plau map to the centromeric end of mouse chromosome 14 (Samuelson and Farber,

TABLE 1

Correlation between Specific Mouse Chromosomes and the IRBP Sequence in 24 Somatic Cell Hybrids

Mouse chromosome

Number of hybrid clones

i-/P -,-a t/p -/+a %

Discordant

1 2 9 2 10 52.2 2 5 8 0 12 48.0 3 1 7 2 8 55.6 4 4 12 1 8 36.0 5 0 14 4 5 39.1 6 5 11 0 9 36.0 7 5 6 0 14 56.0 8 3 13 1 6 30.4 9 5 12 0 7 29.2

10 2 19 3 1 16.0 11 0 14 4 0 22.2 12 3 4 0 11 61.1 13 5 10 0 8 34.8 14 4 19 0 1 4.2 15 2 1 0 13 81.2 16 1 13 3 6 39.1 17 5 6 0 13 54.2 18 1 8 2 10 57.1 19 3 12 1 7 34.8 20 3 9 1 11 50.0

a Symbols indicate the presence (+/) or absence (-/) of the mouse restriction fragments as related to the presence (/+) or ab- sence (/-) of a particular mouse chromosome in the somatic cell hybrids analyzed.

SHORT COMMUNICATION 729

1985; Ceci et al., 1990), and their human homologs (ADK and PLAU) map to human 10 (Francke and Thompson, 1979; Tripputi et al., 1985). We have mapped the mouse gene for IRBP (Rbp-3) to the cen- tromeric region of mouse chromosome 14, and the hu- man homolog (RBP3) maps to chromosome lOq11.2 (Liou et al., 1987; Nickerson et al., 1988). On the other hand, while the mouse gene Np-1 maps to mouse chromosome 14 (Womack et al., 1977), its human ho- molog (NPl) maps to human 14 (Ricciuti and Ruddle, 1973). The positioning of Rbp-3 on the centromeric side of Np-1 is, therefore, supported by the localiza- tion of ADK, PLAU, and RBP3 to human chromo- some 10 and the localization of NP to human chromo- some 14. These data also suggest that the two genes, Rbp-3 and Np-1 on mouse chromosome 14, span an ancestral site of translocation involved in the diver- gent karyotypic evolution of man and mouse.

The standard mouse genetic maps (Lyon, 1989; Da- visson et al., 1989) describe a recombination distance between Np-1 and Es-10 that is approximately half of what we observed in this study. The difference is sta- tistically significant (x2 = 7.65, P < 0.05) and may be related to the fact that our data are based on analysis

FIG. 2. Autoradiogram of a Southern blot of DNAs from paren- tal mice of the interspecific backcross (NFS/N X M. n. muscu- lus)F, X M. m. musculus digested with XbaI and hybridized with IRBP-900 cDNA; each lane has 10 pg of DNA. The arrows show a lO.l-kb fragment unique to M. m. musculus (lane 1) and an 11.4-kb fragment unique to NFS/N (lane 2). DNAs were extracted from mouse livers, cleaved with XboI, run on 0.4% agarose gels, trans- ferred to nylon membranes, and hybridized to labeled probe as described previously (23).

TABLE 2

Segregation of an Rbp-3 Hybridizing Restriction Fragment with Alleles of Np-1 and Es-10 among 102 Backcross Progeny between NFS/N and Mus muscu- lus musculus (Skive)

Inheritance of NFS/N allele

Number of Mice Rbp-3 Np-1 Es-10 prow

Parental + + + 31 - - - 47

Single + + 12 recombinants - - + 9

+ - - 2 - + -t 1

Recombination”

% Recombination Locus pair r/n (+l SE)

(Rbp-3, Np-1 ) 31102 2.9 + 1.7 (Rbp-3, Es-IO) 241102 23.5 + 4.2 (Np-1, Es-IO) 21/102 20.6 + 4.0

’ Percentage recombination between restriction fragments and standard error were calculated according to Green (18) from the number of recombinants (r) in a sample size of n.

of an intersubspecific cross, whereas the linkage dis- tances on the standard maps were defined using in- traspecific crosses. Various studies comparing recom- bination in inter- and intraspecific crosses have sug- gested the existence of “hot spots” that increase the frequency of recombination or of chromosomal rearrangements that interfere with recombination (Hammer et al., 1989; Crosby et al., 1990). The region of mouse chromosome 14 being considered here has been examined in two other studies in which interspe- cific crosses were analyzed. In contrast to our obser- vations, Ceci et al. (1990) reported recombinational data for several markers spanning this same region of mouse chromosome 14 (Rib-l, Tcra, Ctla-1, and hr) and found no deviation from the published maps. However, our result of a greater recombinational fre- quency between Np-1 and Es-10 is comparable to the observation of Crosby et al. (1990). In the analysis of that interspecific backcross, the higher recombina- tion frequency was further limited to the region spanned by the genes TCFU and Np-I, whiIe no signifi- cant difference was found in the region spanned by Tcra and Es-IO. In our study we found no recombi- nants between Tcra and Np-1 in 54 backcross progeny (data not shown), as expected from the standard ge- netic map. This indicates that the higher overall re- combination rate in our cross could not be traced to the Tcra-Np-1 interval.

730 SHORT COMMUNICATION

Our effort to map the gene for IRBP is part of a larger investigation of mouse genes encoding proteins involved in the light response of vision. To date we have mapped the a-, /3-, and y-subunits of cGMP- phosphodiesterase to mouse chromosomes 18, 5, and 11, respectively (Bowes et CL, 1989, 1990; Danciger et al., 1990a, 1989a), the CY- and P-subunits of retinal rod transducin to mouse chromosomes 9 and 4, respec- tively (Danciger et al., 1989b, 199Ob), and the S-anti- gen (48-kDa protein) to mouse chromosome 1 (Dan- tiger et al., 1989c). Another gene in this family, rho- dopsin, has recently been mapped to mouse chromosome 6 (Elliott et al., 1990). In this report we have shown that the gene corresponding to IRBP maps to mouse chromosome 14. Since this region of the mouse genome carries no mutations known to af- fect the retinal photoreceptors (Green, 1989; Davis- son et al., 1989; Lyon, 1989), Rbp-3 (by virtue of its map position) is not at present a candidate for the site of a lesion causing any such inherited abnormalities.

ACKNOWLEDGMENTS

This research was supported by grants to D.B.F. from the Na- tional Retinitis Pigmentosa Foundation (Baltimore, MD), the George Gund Foundation, and NIH Grants EY 02651, EY 08285, and EY 00331. NFS/N mice (derived from Mus museulz~~ domesti- cu.s) were obtained from NIH, Division of Natural Resources (Be- thesda, MD) and Mus musculus musculus from a laboratory colony derived from mice originally trapped in Skive, Denmark, and maintained by Dr. M. Potter (NC1 Contract NOl-CBZ-5584) at Hazelton Laboratories (Rockville, MD).

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