A gene mutated in patients with X-linked hypophosphatemic rickets recently has been described by the HYP consortium (1 ). The gene named PEX (
Two mouse models for hypophosphatemia have been described extensively, Hyp (7 ) and Gy (8 ) mice. Hyp arose as a spontaneous mutation and affected mice show hypophosphatemia, impaired renal tubular phosphate reabsorption and vitamin D non-responsive rickets or osteomalacia, closely resembling human X-linked hypophosphatemic rickets (7 ). The Gy mutation was found among the offspring of an irradiated female mice. In addition to hypophosphatemia, affected Gy males and some affected female animals show circling behavior and inner ear abnormalities. Furthermore, male affected animals are sterile and have reduced viability from birth, with sudden death occurring in adults (8 ). There has been speculation that a subset of X-linked HYP patients with hearing defects may be the counterpart of the Gy phenotype in mouse (9 ).
Both Hyp and Gy loci are known to map to a region of the mouse X chromosome syntenic to the human PEX locus. They have been reported to show a recombination fraction of 0.4-0.8% (8 ). This led to the suggestion that mutations in two different genes, closely situated on the X chromosome and both involved in phosphate metabolism, are responsible for hypophosphatemia.
There have been conflicting reports regarding the biochemical differences between the Hyp and Gy mouse phenotypes. Gy mice have been reported to maintain an appropriate elevation of renal 1 [alpha]-hydroxylase relative to hypophosphatemia (10 ), while Hyp mice manifest only normal, not increased, enzyme activity (11 -13 ). However, elevation of renal 1 [alpha]-hydroxylase levels in Gy mice could not be confirmed by other investigators (14 ). Two types of renal sodium phosphate co-transporters have been cloned (15 ,16 ) and reduced mRNA levels for the type 2 sodium phosphate co-transporter in Hyp (17 ) and Gy (18 ) kidney have been demonstrated. Other investigators, however, found that mRNA levels for this co-transporter were normal although the levels of immunoreactive protein were reduced (19 ). This led to the proposition that the molecular defects in the expression of this co-transporter are distinct in Hyp and Gy mice.
There has also been speculation that Hyp and Gy exhibit strain-related differences since they are present on different background strains. Hyp mice are maintained on a C57BL/6J background, whereas Gy mice are on a B6C3H background. When the Gy mutation is transferred to the C57BL/6J strain, however, male Gy mice do not survive (20 ). Therefore, it seems that interstrain differences alone do not explain the phenotypic and biochemical differences. In summary, it has been widely assumed that Hyp and Gy are different but closely linked loci.
Recently, the sequence of the mouse homolog of PEX and its expression in bone tissue has been described by Du et al. (21 ). No mutations were detected in Hyp mice using a RT-PCR approach, although bone tissue and cultured osteoblasts were found to be negative for Pex expression. Here we report allelic Pex mutations in both Hyp and Gy, thus providing mice models for the human disease.
To obtain the mouse homolog of PEX, we first screened 1 000 000 clones each of a mouse spleen and mouse B-cell library. Only a single unspliced clone (2.9 kb) was obtained from the spleen library corresponding to bp 664-732 (corresponding to human exon 6) of the final mouse sequence.
We then screened a mouse P1 library with human PEX cDNA and isolated two clones 703H24279 and 703B06300. Clone 703H24279 was positive for a cDNA fragment corresponding to bp 1-1079 of the composite mouse sequence, clone 703B06300 to a cDNA fragment corresponding to bp 1900-2148. Positive fragments of the P1 clones (2.9 kb EcoRI-HindIII and 2.5 kb HindIII fragments of 703H24279 and 1.3 and 1.0 kb EcoRI fragments of 703B06300) were subcloned and sequenced. The 2.9 , 2.5, 1.3 and 1.0 kb fragments contained the sequence from bp 191 to 349 (corresponding to human exon 3), 934-1079 (corresponding to human exon 9), 1900-1968 (corresponding to human exon 19) and 2071-2148 (corresponding to human exon 21), respectively. The sequence between these exons was obtained by RT-PCR in mouse cDNA randomly transcribed from white blood cells, 12.5 day total fetal mouse and mouse adult kidney RNA.
To obtain the 5' and 3' end of the gene, we used rapid amplification of cDNA ends (RACE) with 17 day total fetal mouse cDNA as template. PCR fragments of ~800 and 900 bp were generated by 5' RACE and 3' RACE, respectively. Sequencing of the 5' RACE product yielded the missing 5' coding sequence and 530 nucleotides of the upstream sequence. The 3' RACE product yielded the missing 3' coding sequence, 216 bp of the downstream sequence and ended in a CTTTT repeat (Fig. 1 ).
The composite cDNA sequence comprises 2993 nucleotides. The predicted open reading frame (ORF) of 2247 nucleotides encodes a protein of 749 amino acids. The gene is highly conserved between man and mouse. The mouse gene shows 91% identity at the DNA level and 96% identity at the protein level to the human gene (GenBank accession no. U60475). The sequence identity is lower in the intracellular and membrane domain (83% between amino acids 1 and 58) than in the extracellular part (97% between 59 and 749) of the proteins (Fig. 2 ).
In addition to the five Pex exons for which the exon-intron boundaries have been sequenced, the overall exon-intron structure was characterised by assigning Pex exons to single EcoRI and HindIII fragments. Overlapping RT-PCR products corresponding to human exons 1-5 identified 4.5 (exon 1), 11 (exons 2 and 3) and 4.5 kb (exons 4 and 5) EcoRI fragments and 2.7 (exon 1), 5.9 (exon 2), 6.1 (exon 3) and >15 kb (exons 4 and 5) HindIII fragments in control mice. Overlapping RT-PCR products corresponding to human exons 15-22 identified 6.0 (exon 15), 6.5 (exon 16), 4.0 (exons 17 and 18), 1.3 (exon 19), 2.1 (exon 20), 1.0 (exon 21) and 4.5 kb (exon 22) EcoRI fragments in control mice. Three EcoRI fragments (6, 8.1 and >20 kb) were identified by hybridising a RT-PCR product which spans exons 12-15.
Table 1
cDNA sequences corresponding to 5' and 3' Pex exons were shown to be deleted in Gy and Hyp mice, respectively. To determine the intragenic breakpoints, RT-PCR products were hybridised to a mouse genomic DNA panel (Fig. 3 ). The Gy breakpoint was determined to map between exons 3 and 4. The three HindIII fragments corresponding to exons 1-3 are deleted (Fig. 3 a). In Hyp mice, six EcoRI fragments corresponding to exons 16-22 were found to be deleted (Fig. 3 b). The three EcoRI bands that correspond to exons 12-15 were present. Thus, the deletion breakpoint in Hyp lies between exons 15 and 16.
We have mapped the spermine synthase gene distal to PEX. Analysis of human cosmids in this region indicates the distance between spermine synthase and PEX to be ~40 kb. The ORF of the human spermine synthase gene shows the same orientation as PEX. The genomic organisation of the human spermine synthase has been determined independently (GenBank accession no. U53331). The homologous mouse sequence was isolated from an embryonic cDNA library and is highly conserved (GenBank accession no. Y09419). So far we have no evidence that sequences at the 3' end of the spermine synthase gene are deleted in Gy. Sequences of exon 2 and of the 3'-untranslated region (UTR) of the spermine synthase gene can be amplified from Gy genomic DNA (see Materials and Methods).
We have determined the cDNA sequence of the mouse homolog of PEX by isolating genomic clones, subcloning and sequencing positive fragments and performing RT-PCRs between the isolated exons. The PEX gene appears to be weakly or transiently expressed in most tissues, as shown by Northern blot results (1 ) and the rarity of clones found in cDNA libraries. We identified only a single cDNA clone from one million clones screened of a mouse spleen library.
Determination of the genomic structure of five mouse exons and hybridisation of cDNA fragments of various length provide evidence that the genomic organisation of the mouse gene is comparable with the human gene, which covers in total ~220 kb and consists of 22 exons (F. Francis, in preparation). The mouse P1 clone, 703B06300, has an insert size of ~20 kb and contains the exons 19-21. The mouse P1 clone, 703H24279, which was examined most extensively, has an insert size of ~70 kb and contains the first nine Pex exons. The corresponding human exons are encompassed in a genomic region of ~67 kb.
The derived Pex cDNA sequence shows a high homology to its human homolog (Fig. 2 ). This high interspecies sequence conservation is a known characteristic of the neutral endopeptidase family (30 ). Both Pex and its human homolog contain only the 10 cysteines which are conserved throughout the endopeptidase family. They lack the additional cysteine in rat ECE-1 which is known to be involved in homodimerisation (31 ). The determination of the tertiary structure awaits further studies. To date, the three-dimensional structure of members of the M4, M10 and M12 family of metallopeptidases have been determined, but not that of any of the members of the neutral endopeptidase family (25 ).
Recently, the sequence of Pex has also been determined by Du et al. (21 ). No mutation was reported in Hyp mice using a RT-PCR approach. However, no Southern blotting experiments have been performed. The cDNA sequence is identical to the one described here, with the exception of a silent nucleotide substitution at position 2235 from T to C. In the 5'-UTR we found three additional nucleotides at position -149, -158 and -159.
The deletions we have identified in both the Hyp and Gy mice were found to be non-overlapping. While Gy bears a deletion of the first three exons of Pex including upstream sequences, in Hyp mice the last seven exons and downstream sequences of unknown size are deleted. Both deletions are predicted to inactivate the mouse gene fully. The occurrence of a deletion in Gy mice is in accordance with the high frequency of deletions observed in irradiation experiments. The observation of a deletion in the spontaneous Hyp mutation is mirrored by the finding of intragenic deletions in humans which occur at a frequency of ~20%. According to the human genomic sequence, the distance between the Hyp and Gy deletion measures minimally 100 kb. The reported recombination between the Hyp and Gy locus (8 ) must have occurred within this region. Similarly, a translocation breakpoint within the human gene has been identified: a female with hypophosphatemic rickets has been found to have triple X and a balanced translocation between Xp22 and chromosome 6p. The breakpoint on the X chromosome is located within a 14 kb EcoRI fragment which contains exons 17-20 (data not shown).
The Hyp mouse provides a mouse model for X-linked hypophosphatemic rickets in man. Like the mutations in man, the Hyp mutation leads to a non-functional protein. The Hyp phenotype resembles the symptoms observed in the human disease, which are rachitic bone disease and hypophosphatemia arising from impaired renal reabsorption of filtered phosphate.
In contrast to Hyp, the Gy phenotype is more complex. In addition to the changes in phosphate metabolism, male Gy mice exhibit hyperactivity, circling behavior, inner ear abnormalities and sterility. The prevalence of circling behavior increases with age. On the C57BL/6J background male Gy mice do not survive, whereas on the B6C3H viability is decreased compared with normals (20 ). The symptoms of the Gy phenotype could be explained by a contiguous gene deletion syndrome which involves at least one additional gene to Pex. So far, we have no evidence that the spermine synthase gene is deleted in Gy mice. Both 3' and 5' sequences can be amplified by PCR, but a gross rearrangement cannot be excluded. The existence of further genes in between spermine synthase and Pex also cannot be excluded. Interestingly, a form of non-syndromic deafness (DFN6) recently has been linked to Xp22 within a candidate region which encompasses the PEX gene (32 ).
With two mouse models for hypophosphatemic rickets available, functional studies are facilitated. Experiments that profit from the existence of mouse models include expression studies, the search for modifier genes, the testing of hypotheses regarding the pathophysiology of the disease and the testing of novel therapeutic approaches.
DNA from B6C3H a/- +/Y and A/- Gy/Y and C57BL/6J +/Y and Hyp/Y mice were obtained from the Jackson laboratory.
Approximately 1 000 000 clones were plated out from an oligo(dT) mouse spleen (Clontech ML1018a) and a mouse lymphocyte library (Clontech ML1032a). The libraries were screened by filter hybridisation using human PEX cDNAs C2H20, C110E and pac1M21 (1 ) as probes. A single positive phage clone from the spleen library was purified by rescreening.
A human cDNA clone containing the 3'-UTR of spermine synthase was isolated from a selected cDNA library (1 ). This cDNA was used to identify clones in mouse 9 day and 12 day embryonic cDNA libraries (B. Herrmann, unpublished).
P1s were identified by screening human PEX cDNAs C110E and P220L (1 ) against gridded mouse P1 library filters. This P1 library was prepared using MboI partially digested DNA obtained from C57BL/6 female mice spleen (F. Francis, unpublished). The cloning vector was pAd10sacBII and the host strain NS3145 (33 ). Clones (120 000) were picked robotically into microtiter dishes, and arrayed at high densities on filter membranes. Hybridisations with human cDNA clones were performed at low stringency in a 30% formamide hybridisation buffer at 42oC. Washes were performed in 3* SSC, 0.1% SDS for 2× 20 min at 20oC, followed by 2× 20 min at 65oC. P1s were prepared as described (34 ). P1 clones were digested with EcoRI, EcoRI-HindIII, HindIII and PstI (Boehringer Mannheim) and hybridised with human PEX cDNAs C2H20, C110E, C1J6 and P220L. Positive fragments were subcloned into Bluescript II SK +/- (Stratagene) and pUC19 (Gibco BRL) plasmid vectors and sequenced using SK and pUC19 primers. From this sequence, primers (Table 1 ) were designed to amplify the mouse exons.
For RT-PCR, poly(A)+ RNA was prepared from 12.5 day mouse embryo (brain) and adult mice (muscle and bone) by extraction with guanidine isothiocyanate and polystyrene latex particles with covalently linked dT30 oligonucleotides (Qiagen). First strand synthesis was carried out using Pex-specific primers from the 5' and 3' end and reverse transcriptase (Pharmacia). As PCR template, 1-10 ng of first-strand cDNA was used for nested PCR reactions. Cycling profiles included an initial denaturation step (94oC for 5 min) followed by 30 cycles of 94oC for 1 min, 60oC for 1 min, 72oC for 1 min, and a final extension step (72oC for 5 min). The amplification product was used for direct sequencing.
RACE were performed with the ready Marathon cDNA Amplification Kit from 17 day mouse embryo (Clontech). Nested 5' RACE was performed using the adaptor-specific primers AP1 and AP2, and Pex-specific 5' end primers (A1MR: 5'-TCGGCTGACTGATTTCTCCAG-3', E2MR1: 5'-TCCAGCCATCACAAGCAAACC-3'). Nested 3' RACE was performed using AP1 and AP2, and Pex-specific 3' end primers (B11MF0: 5'-TGAAAGGGAAGAGGACCCTG-3', B11MF1: 5'-ATTGCTGATAATGGGGGTCTG-3'). The PCRs were carried out essentially as recommended by the manufacturer. Products were gel purified and sequenced.
PCR-amplified cDNAs, library cDNA clone and genomic fragments cloned into plasmid vectors were purified by PCR purification, gel extraction and plasmid preparation kits (Qiagen). Cycle sequencing was performed using a Taq DyeDeoxy Terminator Cycle sequencing kit (ABI). The sequences were determined with an Applied Biosystems 377 automated sequencer.
For Southern blot analysis, genomic DNA (~5 µg) from mouse inbred strains (C3H/HeJ and C57BL/6J), mouse mutant strains (B6C3H Gy/Y and C57BL/6J Hyp/Y) and backcross strains were digested with EcoRI and HindIII. The digested DNAs were electrophoresed on 0.7 and 1% agarose gels, and blotted to nylon membranes (Hybond-N+, Amersham) by alkaline transfer. Hybridisations were generally performed in a hybridisation buffer containing 1.5* SSPE, 1% SDS and 10% dextran sulfate at 65oC. Probes were labeled by random hexamer priming. Washing was done under stringent conditions (0.1* SSC, 0.1% SDS at 65oC for 15 min).
Primers designed from genomic sequence were used for DNA amplification of Pex exons (Table 1 ). After an initial denaturation for 5 min at 94oC, denaturation was at 94oC for 40 s, annealing at the exon-specific temperature for 40 s, and 40 s extension at 72oC for 30 cycles followed by a final extension for 5 min at 72oC. Reactions (50 µl) contained 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 1.5 mM MgCl2, 0.01% (w/v) gelatine, 160 µM of each dNTP, 0.6 µM of each primer, 0.5 U Taq DNA polymerase (USB), and 100 ng of genomic mouse DNA.
For amplification of spermine synthase, we used primers designed from the cDNA sequence (GenBank accession no. Y09419). Amplification of genomic DNA was performed with primers of exon 2 (SSmF1: 5'-CCAAAGCTGATGGTGAGG-3', SpSyR3: 5'-CATTCTTGTTCGTGTAAGTTGC-3') and of the 3'-UTR (SpSyF1: 5'-TTTTACACTGTTTGGAAGAAAGC-3', SpSyR1: 5'-CTAAGTCAATTTGGGGGTGAG-3').
We thank H. Hellebrand, K. Schughart, T. Guenther and J. Schmidt for their contribution to this study and B. Herrmann for the mouse embryonic cDNA library. The work was supported by grants from the Deutsche Forschungsgemeinschaft, the Commission of the European Communities (CT930027), the NIH (AR42228, AR27032) and the NIA (5 P60 AG11268). F.F. was supported by the Peter und Traudl Engelhorn Stiftung.
Human Molecular Genetics Pages
©
Introduction
Results
Mouse homolog of PEX
Gene structure
Hyp and Gy deletions
Discussion
Materials And Methods
Mice
cDNA library screening
Identification of P1 clones and subcloning
RT-PCR assays and 5' and 3' RACE
Sequencing
Mutation analysis
Acknowledgements
References
Exona
Primer A
Primer B
bp
oC
3
5'-TCTTGTCAAACAGTGTTCTGG-3'
5'-CCAGGGAGACATTTGAGGAG-3'
300
60
6
5'-TGGAGTGAACTTATTTCTTGGG-3'
5'-ACCAAACAGTAGCCAGACAAG-3'
258
60
9
5'-ATCCTGCCTAAAATGCTTTTGC-3'
5'-AAAGCAGGAAAAAGTGCTGC-3'
2000
58
19
5'-GCTTGGGCTAGTTTGCTATCTC-3'
5'-TGAGTTGGTGCTATACACGGAG-3'
304
62
21
5'-CCAAAATTGTTCTTCAGTACACC-3'
5'-ATCTGGCAGCACACTGGTATG-3'
258
64
REFERENCES
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M. J. Econs and F. Francis Positional cloning of the PEX gene: new insights into the pathophysiology of X-linked hypophosphatemic rickets Am J Physiol Renal Physiol, October 1, 1997; 273(4): F489 - F498. [Abstract] [Full Text] [PDF]
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F. Francis, T. M. Strom, S. Hennig, A. Boddrich, B. Lorenz, O. Brandau, K. L. Mohnike, M. Cagnoli, C. Steffens, S. Klages, et al. Genomic Organization of the Human PEX Gene Mutated in X-Linked Dominant Hypophosphatemic Rickets Genome Res., June 1, 1997; 7(6): 573 - 585. [Abstract] [Full Text] [PDF]
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