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Human Molecular Genetics Pages 793-798

Mouse pale ear (ep) is homologous to human Hermansky-Pudlak syndrome and contains a rare `AT-AC' intron
Introduction
Results
Discussion
Materials And Methods
   Hps cDNA and genomic BAC isolation and analysis
   Mutation detection
Acknowledgements
References

Mouse pale ear (ep) is homologous to human Hermansky-Pudlak syndrome and contains a rare `AT-AC' intron

Mouse pale ear ( ep ) is homologous to human Hermansky-Pudlak syndrome and contains a rare `AT-AC' intron Guo Hong Feng, Tu Bailin, Jangsuk Oh and Richard A. Spritz*

Departments of Medical Genetics and Pediatrics, University of Wisconsin, 445 Henry Mall, Madison, WI 53706, USA

Received December 26, 1996; Revised and Accepted February 27, 1997

Hermansky-Pudlak syndrome (HPS) is a rare, often fatal, autosomal recessive disorder in which albinism, bleeding and lysosomal storage are associated with defects of diverse cytoplasmic organelles, including melanosomes, platelet dense granules and lysosomes. Similar multi-organellar defects occur in the Chediak-Higashi syndrome (CHS), as well as in a large number of different mouse mutants. The HPS gene is located in 10q23, and two genetically distinct mouse loci, pale ear (ep) and ruby-eye (ru), both with mutant phenotypes similar to human HPS, map close together in the homologous region of murine chromosome 19, suggesting that one of these loci might be homologous to human HPS. We recently identified the human HPS gene, which encodes a novel ubiquitously-expressed transmembrane protein of unknown function. Here, we describe characterization of the mouse Hps cDNA and genomic locus, and identification of pathologic Hps gene mutations in ep but not in ru mice, establishing mouse pale ear as an animal model for human HPS. The phenotype of homozygous ep mutant mice encompasses those of both HPS and CHS, suggesting that these disorders may be closely related. In addition, the mouse and human HPS genes both contain a rare `AT-AC' intron, and comparison of the sequences of this intron in the mouse and human genes identified conserved sequences that suggest a possible role for pre-mRNA secondary structure in excision of this rare class of introns.

INTRODUCTION

Hermansky-Pudlak syndrome (HPS) is an often fatal, autosomal recessive disorder that, though generally rare, is the most common single-gene disorder in Puerto Rico, where it occurs with a frequency of ~1/1800 (1 ). HPS is characterized by oculocutaneous albinism, bleeding, and lysosomal storage (1 ,2 ), associated with defects of diverse cytoplasmic organelles, including melanosomes (3 -5 ), platelet dense granules (6 -9 ), and lysosomes (10 ,11 ). Similar multi-organellar defects occur in the Chediak-Higashi syndrome (CHS) (12 -15 ), and the relationship between these two phenotypically distinct disorders has long been of interest. Likewise, similar phenotypes and multi-organellar defects are associated with mutations of at least 15 distinct loci in the mouse (16 -18 ), and it seemed likely that one of these murine loci might be homologous to human HPS.

We recently identified the HPS gene (19 ) and showed it to encode a novel, ubiquitiously expressed, transmembrane protein of unknown function. The human HPS gene consists of 18 coding and two 5'-untranslated exons spanning ~30.5 kb (20 ) in chromosome segment 10q23 (21 ,22 ). Two of those mouse loci that exhibit mutant phenotypes similar to human HPS, pale ear (ep) and ruby-eye (ru), map close together in the homologous region of murine chromosome 19 (23 ), suggesting that one or the other might be homologous to human HPS. Though only 1.3 cM apart, ep and ru complement in crosses, and thus are genetically distinct (24 ). To determine whether either ep or ru constitute a mouse model of human HPS, in this study we therefore characterized the mouse Hps cDNA and genomic locus, and used these data as a basis to screen for mutations in DNA of ep and ru mutant mice. We describe the identification of pathologic Hps gene mutations in ep but not in ru mice, establishing mouse pale ear as an animal model for human HPS. The phenotype of homozygous ep mutant mice includes characteristics encompassing those of both HPS and CHS, suggesting that these disorders may be closely related. In addition, the mouse and human HPS genes both contain a rare `AT-AC' intron (25 ), and comparison of the sequences of this intron in the mouse and human genes identified conserved complementary sequences that suggest a possible role for pre-mRNA secondary structure in excision of this rare class of introns.

RESULTS

Screening of a BALB/c mouse pre-B cell cDNA library with the full-length human HPS cDNA (19 ) yielded four different clones, of which the longest was 2.7 kb in size. DNA sequence analysis showed that this cDNA would encode a 703 amino acid (aa), 79.7 kDa polypeptide with 81.2% sequence identity to the human HPS protein (Fig. 1 ). The two predicted transmembrane domains have been almost completely conserved, as has been the 33 aa segment that is subject to alternative RNA splicing in the human (19 ,20 ). The 8 aa segment common to the human HPS and CHS/BG (Chediak-Higashi syndrome) proteins (DKFVKNRG) has been moderately conserved between the human and mouse (DKFIKNRV; residues 436-443) HPS proteins. However, the C-terminal putative melanosomal localization signal (PLL) found in the human HPS polypeptide does not occur in the mouse protein (TLP), casting doubt on the significance of this motif. One region in which there has been considerable divergence is residues 245-267 (murine), in which the mouse HPS protein includes a polyglutamine tract not present in the human protein, resulting from a GAG repeat. The length of this repeat is polymorphic among different mouse strains, with six repeats in BALB/c and seven repeats in 129/SvJ. We found several other differences between the mouse cDNA (derived from BALB/c) and genomic (derived from 129/SvJ; see below) sequences; a total of five resulted in amino acid differences: R31Q, C89Y, 258+E, K567E and S689G (Fig. 1 ). For amino acids 31, 258, and 567, neither of the polymorphic mouse residues correspond to those in the human, whereas amino acid residue 89 is C and 689 is G in the human (19 ).


Figure 1. Alignment of the mouse and human HPS polypeptides. Boxes indicate residue identities. The mouse sequence shown is of strain BALB/c; polymorphisms observed in strain 129/SvJ include R31Q, C89Y, 258+E, K567E and S689G. The human sequence shown is from ref. 16; observed polymorphisms include G283W, P491R, R603Q and V630I (21). The putative transmembrane domains are indicated by heavy horizontal lines. Filled triangles overline indicate the positions of introns. The mouse Hps cDNA sequence has been entered in the GenBank database; accession number U78315.



Figure 2. Potential base-pairing within the AT-AC intron 15 of the mouse Hps gene. Uppercase indicates residues conserved between the mouse and human genes. 5' splice consensus, 3' splice consensus, and branch site consensus sequences are indicated. Dark box indicates conserved complementary hexanucleotide motifs. The complete mouse Hps genomic sequence has been entered in the GenBank database; accession numbers U78954-U78966.

Alignment of the mouse and human HPS cDNA sequences with the human HPS genomic sequence (26 ) allowed us to predict probable locations of introns within the mouse Hps gene. PCR amplification using primer pairs predicted to be in adjacent exons generally confirmed these predictions, and by DNA sequence analysis of a PCR product spanning the last intron we developed a sequence-tagged site with which we screened a mouse bacterial artificial chromosome (BAC) library by PCR. Four clones were identified, BACM-30 (8O) (200 kb), BACM-94 (4B) (120 kb), BACM-177 (13D) (120 kb) and BACM-225 (12E) (120 kb). Restriction enzyme digests indicated that all four BACs were different, though all shared numerous fragments, and exon content analysis by PCR indicated that all four contained both ends of the Hps gene. We carried out direct DNA sequence analysis of BACM-177 (13D) using a series of primers derived from the mouse Hps cDNA sequence, and thereby determined the exon-intron organization of the gene and ~8.3 kb of genomic sequence. As shown in Figure 1 , the mouse Hps gene consists of at least 19 exons, those comprising the coding region separated by introns at virtually the same positions as in the human HPS gene (20 ). However, the human gene contains two 5'-untranslated exons, whereas the mouse gene contains one. As the sequences in the 5'-untranslated regions have been poorly conserved, if at all, and the positions of the introns that interrupt the 5'-untranslated region do not correspond in the human and mouse, we cannot exclude the possibility that the mouse gene includes one or more additional 5'-untranslated exons farther upstream. PCR analysis of mouse genomic DNA indicated that the sizes of the intervening sequences are very similar to those in the human gene, and that the mouse Hps gene spans ~24.1 kb of DNA in toto.

Previous analysis of the human HPS gene (20 ) showed that intron 16 is a member of the extremely rare `AT-AC' class of introns (25 ), characterized by the dinucleotide AT occurring at the 5' end and AC at the 3' end, and a conserved branch site consensus similar to that in yeast, recognized by the minor U11 and U12 snRNPs, respectively (26 ,27 ). The homologous intron 15 of the mouse Hps gene is likewise an AT-AC intron, indicating that this unusual intron predated divergence of the human and murine evolutionary lineages. In addition to the conserved 5' splice, 3' splice, and branch site consensus sequences, comparison of the mouse and human sequences revealed two additional blocks of conservation in this region; a hexanucleotide (5'-AGCCAG-3') just distal to the 5' splice consensus and another (5'-CTGGCT-3') just distal to the branch site consensus (Fig. 2 ). These two conserved motifs are complementary, and in the mouse are flanked by sequences with extensive potential for base-pairing, whereas in the human there is no significant base-pairing potential beyond these conserved motifs (Fig. 2 ). The apparent conservation of these two complementary hexanucleotides suggests that base-pairing of these motifs may function to juxtapose the 5' splice site and branch site of the AT-AC intron in the pre-mRNA, in a manner very reminiscent of splicing of at least some typical pre-mRNA introns in yeast (28 -30 ). Only a very few AT-AC introns have yet been identified, and it remains to be seen whether self-complementary sequences near the splice junctions will turn out to be a frequent feature of this rare class of introns.


Figure 3. Mutations of the Hps gene in homozygous pale ear mutant mice. a and b, Agarose gel electrophoretic analysis of PCR products spanning (a) exon 17 and (b) exon 19. Lanes: 1, ep/ep C57BL/6J; 2, ep6J/ep6J C57BL/6J; 3, C57BL/6J; 4, C3H/HeJ; 5, BALB/c; 6, 129/SvJ; M, molecular size standard. (c) ep6J deletion/insertion mutation. (d) ep IAP insertion; IAP sequence shown is antisense. The ep mutation arose spontaneously on the C3He/FeJ background and was backcrossed to C57BL/6J for 20 generations, inbred for 37 generations, and backcrossed to C57BL/6J for another 10 generations. The ep6J mutation arose spontaneously on the C57BL/6J background and was inbred for 186 generations. Sequences of the ep mutant allele have been entered in the GenBank database, accession numbers U79119 and U79120.

To determine whether either the ep or ru loci correspond to the Hps gene, we carried out PCR amplification of each intron as well as of each exon using primers derived from the adjacent intervening sequences. We analyzed DNA from mice homozygous for each of the two extant ep alleles, ep and ep6J, for each of four ru alleles, ru, ru3J, ru4J, and ru6J, and from wild-type mice of the corresponding genetic backgrounds. Long-range PCR analyses detected no intronic abnormalities in either ru or ep mice. Furthermore, single-strand conformation polymorphism (SSCP) analysis of Hps exonic PCR products amplified from DNAs of the four ru mutants identified no apparent abnormalities (data not shown). However, simple agarose gel electrophoresis of the exonic PCR products demonstrated obvious abnormalities in both of the ep mutants: of exon 17 in ep6J, and of exon 19 in ep. As shown in Figure 3 a, the ep6J exon 17 PCR product was smaller than normal, whereas the ep exon 19 PCR product was ~5.5 kb larger than normal (Fig. 3 b), and Southern blot hybridization analysis of ep genomic DNA demonstrated aberrant bands suggestive of a ~5.5 kb insertion in this region (not shown). These abnormalities were not seen in DNAs of mice from the corresponding genetic backgrounds (Fig. 3 ). Direct DNA sequence analysis of the ep6J exon 17 PCR product demonstrated a complex 23 bp deletion/3 bp insertion involving codons 611-618 that introduces a translational terminator at this site (Fig. 3 c). Direct DNA sequence analysis of the ep exon 19 PCR product demonstrated a 7 bp `target' duplication of codons 655-657 (ACTACAG) flanking insertion of an intracisternal A particle (IAP) element, with the long terminal repeats (LTRs) in the antisense transcriptional orientation (31 ,32 ) (Fig. 3 d). This would result in a 92 aa nonsense polypeptide distal to S657 and translational termination within the IAP element. Thus, both the ep6J and ep mutations would abolish production of full-length Hps protein from the mutant alleles, as would all human HPS mutations reported to date (19 ).

DISCUSSION

Ruby-eye (ru) and pale ear (ep) are among ~15 distinct mouse loci with recessive mutant phenotypes that include hypopigmentation associated with defects of multiple cytoplasmic organelles, including melanosomes, lysosomes, and granular elements of platelets (17 ,18 ). Similar phenotypes occur in human Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS). HPS has recently been associated with mutations of the HPS gene (19 ), whereas CHS results from mutations of the CHS1 gene (33 ,34 ), which is homologous to the beige (bg) locus of mice (33 ,35 ). In this study we characterized Hps, the mouse homologue of the human HPS gene, and looked for mutations of this gene in DNAs of ru and ep mutant mice. We found no abnormalities of the Hps gene in ru mutant mice, but found pathologic mutations in both extant ep alleles, demonstrating that the mouse pale ear locus corresponds to the Hps gene. Our identification of Hps gene mutations in ep but not ru mutant mice seems somewhat surprising, since the phenotype of ru mutant mice is very similar to that of human HPS, whereas that of ep mutant mice is similar to human HPS, but also includes substantial differences. Like human HPS, homozygous pale ear mutant mice exhibit reduced pigmentation (34 ,35 ), have aberrant retinofugal neuronal projections typical of albinism (37 ,38 ), and at the cellular level manifest mild structural abnormalities of melanosomes (37 ), abnormalities of lysosomal function (39 -41 ), and a `storage pool deficiency' of platelets due to deficient dense granules (42 ,43 ). However, unlike human HPS, as the name implies, hypopigmentation in pale ear mice is principally evident in the ears and tail. Differential ear hypopigmentation has not been remarked on in human HPS, and of course evaluation of tail pigment in humans would be challenging. Furthermore, homozygous pale ear mutant mice also exhibit reduced natural killer (NK) cell activity (40 ) and complex immune deficits (44 ,45 ) not found in human HPS (46 ) but which are a prominent feature of the Chediak-Higashi syndrome and in mice with the homologous disorder, beige (bg). Thus, though mouse pale ear is homologous to human HPS, its phenotype bridges the gap between HPS and CHS/beige, indicating that the pathophysiologic relationship between these two similar disorders may be even closer than was previously realised. It has been suggested that the CHS/beige gene product may be involved in trafficking of intracellular proteins to the lysosome, late endosome, and perhaps other cellular compartments (35 ,47 ), and it may thus be that the HPS/Hps and CHS/beige proteins are both involved in a common mechanism or pathway of intracellular protein sorting.

MATERIALS AND METHODS

Hps cDNA and genomic BAC isolation and analysis

A cDNA library from BALB/c mouse pre-B-cell line 22D6 was screened by hybridization to full-length human HPS cDNA (19 ). Inserts were sized and the sequence of the largest cDNA (2.7 kb) was determined completely on both strands. The mouse Hps cDNA sequence was aligned with HPS genomic sequence to predict probable intron locations, and oligonucleotide primers derived from the mouse cDNA were used to estimate intron sizes by long-range PCR. The PCR product spanning intron 18 was sequenced completely on both strands and used to design a 188 bp STS that was used to screen a 129/SvJ mouse BAC library (Genome Systems). BACs were analyzed by restriction cleavage and exon content mapping by PCR. To determine Hps genomic sequences, primers from within predicted exons were used to directly sequence BACM-177 (13D); additional primers were designed from intron sequences to determine sequences on both strands. All DNA sequencing was carried out by manual cycle-sequencing, and DNA sequences were assembled and analyzed using the DNAStar software package.

Mutation detection

Genomic DNAs of homozygous ep, ep6J, ru, ru3J, ru4J and ru6J mutant mice, and of wild-type mice of corresponding strains C57BL/6J and C3H/HeJ were purchased from the Jackson Laboratories. DNA of BALB/c mice was provided by Dr W. Dove. All DNAs were screened for mutations in parallel. Intron sizes were assayed by long-range PCR using cDNA primers, and exons were analyzed by PCR amplification using primers derived from the adjacent introns followed by non-radioactive SSCP analysis in MDE gels (AT Biochem) as described (48 ). The sizes of the ep6J exon 17 and ep exon 19 PCR products were obviously abnormal on agarose gel electrophoresis, and these were reamplified, purified using the Gel Extraction Kit (Qiagen), and subjected to direct, manual cycle-sequencing. In addition, ep/ep, C57BL/6J, and C3H/HeJ DNA were digested with EcoRI, HindIII, and SacI and analyzed by Southern blot hybridization using a 0.9 kb probe spanning Hps exon 18, IVS18, and exon 19.

ACKNOWLEDGEMENTS

We thank Dr J. Petrini for providing the BALB/c mouse cDNA library, Dr W. Dove for BALB/c mouse DNA, and Drs J. Petrini and M. Mahadevan for comments on the manuscript. This work was supported by Clinical Research Grant 6-0281 from the March of Dimes Birth Defects Foundation and Grant AR-39892 from the National Institutes of Health. This is paper 3480 from the Laboratory of Genetics, University of Wisconsin.

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*To whom correspondence should be addressed. Tel: +1 608 262 2832; Fax: +1 608 262 2976; Email: raspritz@facstaff.wisc.edu

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