Chromosomal Localization and Genomic Organization of Genes Encoding Guanylyl Cyclase Receptors Expressed in Olfactory Sensory Neurons and Retina

GENOMICS

31, 367 –372 (1996) 0060

ARTICLE NO.

Chromosomal Localization and Genomic Organization of Genes Encoding Guanylyl Cyclase Receptors Expressed in Olfactory Sensory Neurons and Retina RUEY-BING YANG,* HANS-JU¨RGEN FU¨LLE,*,†

AND

DAVID L. GARBERS*,†,1

†Howard Hughes Medical Institute and *Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9050 Received June 19, 1995; accepted October 26, 1995

We recently cloned three membrane guanylyl cyclases, designated GC-D, GC-E, and GC-F, from rat olfactory tissue and eye. Amino acid sequence homology suggests that they may compose a new gene subfamily of guanylyl cyclase receptors specifically expressed in sensory tissues. Their chromosomal localization was determined by mouse interspecific backcross analysis. The GC-D, GC-E, and GC-F genes (Gucy2d, Gucy2e, and Gucy2f ) are dispersed through the mouse genome in that they map to chromosomes 7, 11, and X, respectively. Close proximity of the mouse GC-D gene to Omp (olfactory marker protein) and Hbb (hemoglobin bchain complex) suggests that the human homolog gene maps to 11p15.4 or 11q13.4– q14.1. The human GC-F gene was localized to the long arm of chromosome Xq22 by fluorescence in situ hybridization. The genomic organization of the mouse GC-E gene was determined and compared to other guanylyl cyclase genes. The mouse GC-D, GC-E, and GC-F genomic clones contain identical exon– intron boundaries within their extracellular and cytoplasmic domains, demonstrating the conservation of the gene structures. With respect to human genetic diseases, GC-E mapped to mouse chromosome 11 within a syntenic region on human chromosome 17p13 that has been linked with loci for autosomal dominant retinitis pigmentosa and Leber congenital amaurosis. No apparent disease loci have been yet linked to the locations of the GC-D or GC-F genes. q 1996 Academic Press, Inc.

INTRODUCTION

Guanylyl cyclases catalyzing the production of cGMP from GTP are classified as soluble and membrane forms (Garbers, 1992; Garbers and Lowe, 1994). The membrane guanylyl cyclases, termed guanylyl cyclases A–F (GC-A, GC-B, GC-C, GC-D, GC-E, and GC-F), Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession Nos. L41933, L44108– L44117, and L47643 –L47646. 1 To whom correspondence should be addressed. Telephone: (214) 648-5090. Fax: (214) 648-5087.

form a family of cell-surface receptors with a similar topographic structure: an extracellular ligand-binding domain, a single membrane-spanning domain, and an intracellular region that contains a protein kinase-like domain and a cyclase catalytic domain (Garbers and Lowe, 1994). GC-A and GC-B function as receptors for natriuretic peptides (Chinkers et al., 1989; Schulz et al., 1989), and GC-C encodes a heat-stable enterotoxin/ guanylin peptide receptor (Schulz et al., 1990). Recently, we cloned an additional membrane guanylyl cyclase (GC-D) from a rat olfactory cDNA library (Fu¨lle et al., 1995) and two guanylyl cyclases (GC-E and GC-F) from a rat eye cDNA library (Yang et al., 1995). GC-D is specifically expressed in a subpopulation of olfactory sensory neurons (Fu¨lle et al., 1995). The rat GC-E and GC-F genes, which may be homologs of recently cloned human cDNAs (Shyjan et al., 1992; Lowe et al., 1995), are expressed in retina (unpublished data). Based on the similarity within their extracellular domains, these three guanylyl cyclases appear to define a new subfamily of guanylyl cyclase receptors, possibly restricted to sensory tissues (Yang et al., 1995; Fu¨lle et al., 1995). Ligands known to activate guanylyl cyclases failed to stimulate the cyclase activity of the sensory forms, and therefore these newly cloned guanylyl cyclases remain orphan receptors (Yang et al., 1995; Fu¨lle et al., 1995). Three members of the natriuretic peptide receptor/ guanylyl cyclase gene family, GC-A, GC-B (also referred to as atrial natriuretic peptide receptors, ANPRA and ANPRB or NPR1 and NPR2), and ANPRC (a protein encoding only the ligand-binding, transmembrane, and 37-amino-acid cytoplasmic domains), have been localized to human chromosomes 1q21 –q22, 9p12 –p21, and 5p13 –p14, respectively (Lowe et al., 1990). Genes encoding subunits of soluble guanylyl cyclase, a3 and b3, have been colocalized to human chromosome 4q31.3 –q33 (Giuili et al., 1993). Recently, a retinal guanylyl cyclase gene, the possible human homolog of GC-E, was mapped to chromosome 17p13.1 (Oliveira et al., 1994). In this report, mouse interspecific backcross analyses

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were used to define the chromosomal localization of the GC-D, GC-E, and GC-F genes (locus designations Gucy2d, Gucy2e, and Gucy2f, respectively). They are distributed on mouse chromosomes 7, 11, and X, suggesting that they did not evolve by tandem gene duplication. The GC-F locus was further localized to the long arm of human chromosome X (q22) by fluorescence in situ hybridization (FISH). The conserved genomic organization of these genes further supports the idea that GC-D, GC-E, and GC-F form a subfamily of guanylyl cyclase receptors expressed in sensory tissues. MATERIALS AND METHODS Probes. To ensure that probes were specific to each gene, cDNA fragments corresponding to the extracellular domains of individual cyclases were used as probes for interspecific backcross analysis. This region is most diverse among the members of the guanylyl cyclase receptor family. To perform FISH, a human P1 clone that was isolated by PCR screening with GC-F-specific primers (5*-tcg cct tgt tct ctg gtt tg-3 * and 5*-cat gac agt tac aag cac cc-3 *) was used (Genome Systems Inc., St. Louis, MO). Interspecific backcross mapping. The interspecific backcross DNA panel was obtained from the Jackson Laboratory (Rowe et al., 1994). This panel contains 94 N2 animals by mating (C57BL/6J 1 SPRET/ Ei)F1 female and SPRET/Ei male and two parental DNAs from C57BL/6J and Mus spretus. The restriction fragment length polymorphism was determined by Southern blots using restriction-enzymedigested parental DNAs. The GC-D probe revealed a ú12-kb NdeI fragment with C57BL/6J and 6- and 7-kb NdeI fragments with M. spretus DNA. The GC-E probe detected a 5.5- and 9-kb BamHI fragment with C57BL/6J and M. spretus parental DNA, respectively. Using the GC-F probe, a 2.2-kb NsiI fragment was detected with C57BL/6J but not with M. spretus DNA. The presence of C57BL/6Jspecific fragments was then used for typing the backcross analyses. The pattern of allele segregation was compared to that of loci previously typed with this panel. Locus position and linkage distance were estimated based on the calculated recombination frequency in pairwise combination (Rowe et al., 1994). No double crossovers were found in typing any of the three cyclase loci. The comparative maps of human and mouse chromosomes for this paper were retrieved from the Mouse Genome Database, the Mouse Genome Informatics Project, The Jackson Laboratory (Bar Harbor, ME; World Wide Web URL: http://www.informatics.jax.org, January, 1995). Fluorescence in situ hybridization. Purified DNA from a P1 clone containing the human GC-F gene was labeled with biotin– dUTP by nick-translation. Labeled probe was combined with sheared human DNA and hybridized to normal metaphase chromosomes derived from phytohemagglutinin-stimulated peripheral blood lymphocytes from a normal male donor in a solution containing 50% formamide, 10% dextran sulfate, and 21 SSC. Specific hybridization signals were detected by incubating the hybridized slides in fluoresceinated avidin. The chromosomes were then counterstained with propidium iodide and analyzed. This experiment resulted in the specific labeling of the long arm of a single group C chromosome in initial experiments. Cohybridization of the X chromosome centromere-specific probe DXZ1 with the P1 probe resulted in the specific labeling of the centromere and the long arm of the X chromosome. Measurements of 10 specifically hybridizing X chromosomes demonstrated that the P1 probe was located at 49% of the distance from the centromere to the telomere of the X chromosome, an area corresponding to band Xq22. A total of 80 metaphase cells were analyzed, with 67 exhibiting specific labeling (Genome Systems Inc.). Isolation and characterization of genomic clones. A phage (l Fix II) mouse genomic library (Stratagene) was screened with 32P-labeled cDNA probes, and positive clones were isolated according to the manufacturer’s suggestions. The genomic fragments that hybridized with the cDNA probes were further subcloned into pBluescript II KS (Stratagene) and sequenced by the Prism kit (Applied Biosystems) on an

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FIG. 1. Mapping of GC-D, GC-E, and GC-F genes on mouse chromosomes 7, 11, and X, respectively. Partial linkage maps indicating the location of three guanylyl cyclase genes (underlined) in relation to linked loci and markers are shown. Genetic distances between loci in centimorgans are given to the left of the chromosome maps. Corresponding loci on human chromosomes are shown to the right of the chromosome maps. ABI Model 373A DNA automated sequencer. Sequence data were analyzed and assembled by the LASERGENE software (DNASTAR Inc., Madison, WI). Sequence data for mouse GC-D, GC-E, and GCF reported in this paper have been deposited with the GenBank database under Accession Nos. L47643 –L47646, L41933, and L44108– L44117, respectively.

RESULTS AND DISCUSSION

Mouse Chromosome Mapping The mouse chromosomal localization of three members of the guanylyl cyclase receptor gene family was determined by interspecific backcross analysis using progeny derived by mating (C57BL/6J 1 SPRET/Ei)F1 female and SPRET/Ei male mice (Rowe et al., 1994). This panel has been typed for more than 451 loci and is anchored by 49 simple sequence length polymorphism loci, 43 proviral loci, and 60 gene sequence loci among the autosomes as well as the X chromosome (Rowe et al., 1994). Our mapping results indicate the dispersal of this gene subfamily in the mouse genome, i.e., the GC-D, GC-E, and GC-F genes map to chromosomes 7, 11, and X, respectively (Fig. 1). This finding is reminiscent of the diverse chromosomal distribution of three members of the natriuretic peptide receptor/ guanylyl cyclase genes in the human genome (Lowe et al., 1990). Each locus is separated from the others and located at different chromosomal regions, suggesting that guanylyl cyclase receptors did not evolve by tandem duplication events. The GC-D gene, which is expressed specifically in olfactory sensory neurons, was localized to the distal region of mouse chromosome 7 linked to D7Hun10, Iapls3-30 (intracisternal A particle, lymphocyte-specific), and D7Mit37 (Fig. 1). Locus order and genetic distances in centimorgans were estimated from the recombination frequencies for each pair of loci. The D7Mit37 marker was used as an anchor to position the

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Gucy2d locus near the Omp (olfactory marker protein) and the Hbb (hemoglobin b-chain complex) loci on the composite linkage map of mouse chromosome 7 (Nadeau et al., 1995). Interestingly, a cluster of seventransmembrane domain odorant receptor genes has been mapped to this region as well (R. Axel, New York, pers. comm.). The mapping of the mouse GC-D gene proximal to Omp and Hbb suggests that the human homolog gene could map to 11p15.4 or 11q13.4 –q14.1 (Brown et al., 1992). The GC-E locus (Gucy2e) was assigned to the central part of mouse chromosome 11 and is closely linked to D11Mit4 (Fig. 1). In a recent report, recoverin (Rcvrn) was located at the D11Mit4 position (McGinnis et al., 1993). The close proximity of the GC-E and recoverin loci is consistent with the recently determined colocalization of their apparent human homologs at chromosome 17p13.1 (Oliveira et al., 1994; Murakami et al., 1992; Wiechmann et al., 1994). Recoverin is a calciumbinding protein expressed in retina and was originally considered as an activator for retinal guanylyl cyclases (Dizhoor et al., 1991; Hurley et al., 1993). Recent studies, however, have demonstrated that retinal guanylyl cyclase is indeed activated by other calcium-binding proteins, termed guanylyl cyclase-activating proteins (GCAPs) (Gorczyca et al., 1994; Gorczyca et al., 1995). A GCAP gene was recently mapped to the short arm of chromosome 6 (p21.1) and may be identical with a new locus for autosomal recessive retinitis pigmentosa (Subbaraya et al., 1994; Knowles et al., 1994). The GC-F gene was mapped to the distal region of mouse chromosome X between DXBir16 and DXMit34 (Fig. 1). The DXMit34 marker anchors the Gucy2f locus close to the Alas2 (d-aminolevulinate synthase) and the Col4A5 (type IV collagen a chain) loci. This suggested the location of the human GC-F gene to be on Xp11.22 or Xq22 (Cotter et al., 1992; Vetrie et al., 1992). Chromosomal Localization of the Human GC-F Gene To determine further the subchromosomal localization of the human GC-F gene, we performed FISH using a probe derived from a human GC-F P1 clone. A representative hybridization of human GC-F P1 DNA (arrow) and the X chromosome centromere-specific probe DXZ1 (arrowhead) is shown in Fig. 2A. Cohybridization with DXZ1 confirmed the localization of the human GC-F locus on chromosome X in the central region of the long arm corresponding to band Xq22 (Fig. 2B). This is consistent with the mouse chromosomal mapping and the fact that a YAC clone encompassing the human GC-F gene also contained the marker DX1210, which is closely linked to Xq22 (data not shown). Genomic Organization of the Mouse GC-E Gene The genomic organization of the mouse GC-E gene was determined from two phage clones that covered the entire coding sequences. The mouse GC-E gene contains 19 exons and 18 introns in its 5*-noncoding and coding regions, spanning a minimum of 16 kb (Fig. 3).

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All splice junction sequences for the donor and the acceptor are in agreement with the GT/AG rule (Table 1). Exon sizes range from 85 to 739 nucleotides, yielding an open reading frame of 3324 nucleotides encoding 1108 amino acids (Table 1; GenBank Accession No. L41933). The predicted mature mouse GC-E protein shares about 96, 87, and 87% identity with its apparent rat, human, and bovine homologs, respectively (Yang et al., 1995; Shyjan et al., 1992; Goraczniak et al., 1994). Furthermore, the organization of the three most 3* exon/introns is identical between the human and the mouse GC-E genes (Oliveira et al., 1994). Therefore, it is likely that the structure of the GC-E gene is highly conserved in the human and mouse genomes. The separation of exons in the mouse GC-E gene corresponds to the structural and functional domains of membrane guanylyl cyclases; i.e., the extracellular domain is distributed among three exons, the single membrane-spanning domain is encoded by one exon, and the kinase-like domain and C-terminal cyclase catalytic domain each are encoded by seven exons (Table 1 and Fig. 3). Interestingly, the positions of introns within the intracellular but not the extracellular regions are very similar to those found in the GC-A gene (Yamaguchi et al., 1990). This supports the hypothesis that all membrane guanylyl cyclase genes are derived from a common ancestral gene harboring kinase-like and cyclase catalytic domains. In addition, GC-D, GCE, and GC-F genes also share identical intron–exon boundaries within their extracellular domains (Table 2). The GC-A gene organization is different within this region. Based on cDNA sequence comparisons and expression studies, it has been suggested that there may exist a family of ligands or regulatory molecules that remains to be identified for this subfamily of sensory guanylyl cyclase receptors (Fu¨lle et al., 1995; Yang et al., 1995). The distinct gene structure shared by GCD, GC-E, and GC-F, especially in their extracellular protein domains, further supports this view. The GC-E and GC-F Genes as Candidates for Retinopathies Photoreceptor expression of two guanylyl cyclases in human and monkey retina has been demonstrated by in situ hybridization or immunocytochemistry (Shyjan et al., 1992; Liu et al., 1994; Lowe et al., 1995), however, there is as yet no direct evidence for the involvement of GC-E and GC-F in phototransduction. If these cyclases are indeed responsible for light adaptation and recovery of the dark state, defects in either the GC-E or the GC-F gene could disrupt synthesis of cGMP and impair the normal function of photoreceptors. Previously, defects of retinal proteins involved in cGMP metabolism have been linked to several retinopathies in animal and human models (Humphries et al., 1992). For example, mutations of rhodopsin (Dryja et al., 1990), phosphodiesterase b subunit (Bowes et al., 1990; Pittler and Baehr, 1991), and rod cGMP-gated channel protein (McGee et al., 1994) have been reported in some forms of autosomal retinitis pigmentosa (RP).

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FIG. 2. Localization of the human GC-F gene to chromosome Xq22 by FISH. (A) Metaphase chromosome spreads from a normal male donor were probed with a human GC-F P1 clone DNA and the chromosome X centromeric probe DXZ1. The identity of the chromosome was verified by cohybridization of the P1 clone DNA (arrow) with the chromosome X centromeric probe DXZ1 (arrowhead). (B) Idiogram of the human chromosome X and position of the human GC-F gene (arrow).

RP comprises a genetically and clinically heterogeneous group of retinopathies in human that can be inherited in an autosomal dominant (ADRP), an autosomal recessive, or an X-linked (XLRP) fashion (Humphries et al., 1992). RP is characterized by progressive degeneration of photoreceptors, which leads to tunnel vision, night blindness, and ultimately to complete loss of vision. Recently, a new locus for ADRP and a gene for Leber congenital amaurosis (LCA) have been mapped to the distal

short arm of chromosome 17 by linkage analysis (Greenberg et al., 1994; Camuzat et al., 1995). The human homolog of GC-E (retGC-1) and recoverin are among the retinal proteins mapped to 17p13.1 (Oliveira et al., 1994; Murakami et al., 1992). While the recoverin gene has been ruled out as a candidate for this form of ADRP and LCA (Greenberg et al., 1994; Camuzat et al., 1995), this raises the possibility that a defect in the GC-E gene might be responsible for a form of ADRP or LCA.

FIG. 3. Structure of the mouse GC-E gene. Exons are indicated by boxes with numbers. Two genomic clones (E5 and EC1) that cover the entire coding sequence of the GC-E gene are shown at the bottom. The extracellular domain is encoded by exons 2 –4, and exon 5 corresponds to the transmembrane domain. The kinase-like and cyclase catalytic domains are encoded by exons 6 –12 and 13– 19, respectively.

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TABLE 1 Exon/Intron Boundary Sequences of the Mouse GC-E Gene Exon/ intron No.

Functional domaina

3*-splice siteb

5*-splice site

Exon size (bp)

Intron size (bp)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

EC EC EC TM KL KL KL KL KL KL KL CC CC CC CC CC CC CC

ttacag/AAGAGG. . . ccgcag/TA GTG. . . ctgcag/GTC TCT. . . cttcag/GG GTG. . . caccag/G CAC. . . cctcag/GTG GTC. . . ttgcag/GGG GAC. . . tttcag/CTT CGA. . . tctaag/GGA ATG. . . tcttag/AT CAG. . . ctctag/AA GTA. . . tcctag/TTC AAG. . . tcctag/A TCT. . . ccccag/GTG GAA. . . ccccag/GC CCG. . . cctcag/CT TAC. . . ctccag/GGC AAG. . . ctgcag/G GCC. . .

. . .TTTCCG/gtaagt . . .AGA G/gtaagc . . .AAG CAG/gtagat . . .GGA G/gtgagg . . .TTG AG/gtgagt . . .CGA AAG/gtcagc . . .TAT GAG/gtaagt . . .TCC AAG/gtgaga . . .ATC AAG/gtgagt . . .GAG G/gtagga . . .GAG G/gtaagg . . .GAC CTG/gtcagg . . .CCT CC/gtgggt . . .TAT AAG/gtggag . . .TCA G/gtaact . . .CTG C/gtgagt . . .CTG AAG/gtgagt . . .CCA GG/gtgagt . . .GGACAG/gtatcg

ú60 739 305 352 85 103 102 81 207 157 150 149 164 193 175 99 95 86 111

292 93 Ç2500 Ç330 Ç250 Ç370 Ç1400 Ç1700 Ç210 Ç490 Ç1200 Ç990 Ç80 Ç360 Ç360 Ç120 Ç140 Ç190

a

Exons coding for the extracellular (EC), transmembrane (TM), kinase-like (KL),and cyclase catalytic (CC) domains. The exonic and intronic sequences are in uppercase and lowercase letters, respectively. The gt/ag consensus sequences of splice junctions are underlined. b

Mapping of the mouse GC-F gene to the X chromosome and the apparent heterogeneity of XLRP loci in human prompted us to map the human GC-F gene. Localization of the GC-F locus on the long arm of human chromosome Xq22, however, is apparently segregated from two major XLRP loci (RP2 and RP3) at Xp11.3–p11.23 and Xp21.1, respectively (Ott et al.,

1990; Coleman et al., 1990). Since mutations for 20 of 40 XLRP families could not be assigned to either the RP2 or the RP3 locus (Teague et al., 1994), it is likely that additional XLRP loci exist, with the GC-F locus being one candidate.

TABLE 2

We thank Deborah E. Miller and Lynda Doolittle for technical assistance. We also thank Lucy R. Rowe and Mary B. Barter (The Jackson Laboratory) for help in the interspecific backcross panel analysis.

Intron Positions of the Mouse GC-D, GC-E, and GC-F Genes

ACKNOWLEDGMENTS

Amino acid interrupteda

REFERENCES

Intron No.

GC-D

GC-E

GC-F

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

. I le -190 Gln Val-289 G ly -407 Ar g -435 —b — — — — — — — — — — — —

. V al -190 Gln Val-292 G ly -409 Ar g -437 Lys Val-472 Glu Gly-506 Lys Leu-533 Lys Gly-602 A sp -654 G lu -704 Leu Phe-754 Pr o -808 Lys Val-873 G ly -931 P ro -964 Lys Gly-996 Gl y -1024

. I le -194 Gln Val-295 — — — — — Lys -606 — G lu -709 Leu Phe-759 Pr o -813 Lys Val-878 G ly -936 P ro -969 Lys -1000 —

a Amino acids are numbered beginning with the predicted signal cleavage site (Fu¨lle et al., 1995; Yang et al., 1995). b Boundary sequences are not determined.

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