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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 8 3840-3844
Copyright © 2001 by The Endocrine Society

Other Original Articles

X-Linked Hypophosphatemia Attributable to Pseudoexons of the PHEX Gene

Paul T. Christie, Brian Harding, M. Andrew Nesbit, Michael P. Whyte and Rajesh V. Thakker

Molecular Endocrinology Group (P.T.C., B.H., M.A.N., R.V.T.), Nuffield Department of Medicine, Level 7, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom; and Metabolic Research Unit (M.P.W.), Shriners Hospitals for Children, and Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri 63131 and 63110

Address all correspondence and requests for reprints to: Prof. R. V. Thakker M.D., F.R.C.P., F.R.C.Path., F.Med.Sci., Molecular Endocrinology Group, Nuffield Department of Medicine, Level 7, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom. E-mail: rajesh.thakker{at}ndm.ox.ac.uk

Abstract

X-linked hypophosphatemia is commonly caused by mutations of the coding region of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). However, such PHEX mutations are not detected in approximately one third of X-linked hypophosphatemia patients who may harbor defects in the noncoding or intronic regions. We have therefore investigated 11 unrelated X-linked hypophosphatemia patients in whom coding region mutations had been excluded, for intronic mutations that may lead to mRNA splicing abnormalities, by the use of lymphoblastoid RNA and RT-PCRs. One X-linked hypophosphatemia patient was found to have 3 abnormally large transcripts, resulting from 51-bp, 100-bp, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a mutation (g to t) at position +1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel donor splice site and 3 preexisting, but normally silent, acceptor splice sites within intron 7 resulted in the occurrences of the 3 pseudoexons. This represents the first report of PHEX pseudoexons and reveals further the diversity of genetic abnormalities causing X-linked hypophosphatemia.

HYPOPHOSPHATEMIC (vitamin D-resistant) rickets [X-linked hypophosphatemia (XLH) or hypophosphatemia (HYP), mendelian inheritance in man number 307800] is the commonest heritable form of rickets and is usually transmitted as an X-linked dominant disorder (1, 2). However, autosomal inheritance of hypophosphatemic rickets has also been reported, and one form, which has been localized to chromosome 12p13.3 is caused by mutations in fibroblast growth factor 23, FGF23 (3, 4). XLH is clinically characterized by childhood rickets (which is not responsive to physiological doses of vitamin D), growth retardation, and poor dental development (2). Affected individuals have hypophosphatemia because of a renal tubular defect, decreased intestinal absorption of calcium, and inappropriately low serum 1,25-dihydroxy-vitamin D concentrations; the serum concentrations of calcium, PTH, and 25-hydroxy-vitamin D are typically normal (2, 5). The gene associated with XLH, which is located on chromosome Xp22.1 (6), has been identified and is referred to as the PHEX (phosphate-regulating gene with homologies to endopeptidases on the X-chromosome) gene (7). PHEX encodes a 749-amino-acid protein that putatively consists of 3 domains, which are: a small aminoterminal intracellular tail; a single, short transmembrane domain; and a large carboxyterminal extracellular domain that contains 10 conserved cysteine residues and a HEXXH pentapeptide motif that characterizes many zinc metalloproteases (8). PHEX mutations, which are likely to result in a functional loss, cause XLH (7, 9, 10, 11, 12, 13, 14, 15, 16, 17). The reported PHEX mutations (>160) in XLH patients (7, 9, 10, 11, 12, 13, 14, 15, 16) are scattered throughout the putative 700-amino-acid extracellular domain, which is encoded by exons 2–22, and are also diverse (consisting of deletions, insertions, duplications, splice site, and nonsense and missense mutations). In addition, one mutation within the 5' untranslated region (UTR) has also been identified (12). However, PHEX mutations have not been detected in about 35% of XLH patients (12, 14), and such patients may harbor mutations in the 3' UTR, or promoter, or intronic regions. We have therefore investigated 11 unrelated XLH patients, in whom coding region mutations had been excluded (12), for intronic mutations that may result in mRNA splicing abnormalities.

Materials and Methods

Patients

Eleven unrelated XLH patients (10 males and 1 female) in whom coding region mutations had been previously excluded (12), were investigated. The diagnosis of XLH was based on the criteria previously described (12), and a family history of XLH was established for all of the patients. Venous blood samples were obtained after informed consent. These studies had received approval from the Ethical Committee of The Hammersmith Hospital, London, UK, and from the Human Studies Committee of the Washington University School of Medicine, St. Louis, MO.

DNA sequence analysis of the PHEX gene

RNA was extracted from Epstein-Barr virus transformed lymphoblastoid cell lines obtained from the peripheral blood cells of the patients from each XLH family, using methods previously described (12, 18). DNA from leukocytes was prepared by standard methods (12, 19). Also, mRNA splicing abnormalities were initially sought in each of the probands, by RT-PCR amplification, using 6 sets of nested primers (12) and lymphoblastoid RNA as described (18). The RT-PCR products from each proband were then gel purified, and the DNA sequences of abnormal products were determined by Taq polymerase cycle sequencing and a semiautomated detection system (ABI 373XL sequencer; PE Applied Biosystems, Foster City, CA) (12, 18). DNA sequence abnormalities were confirmed by allele-specific oligonucleotide (ASO) hybridization analysis (12, 13, 14, 15, 16, 17, 18, 19). In addition, the DNA sequence abnormalities were confirmed and demonstrated to cosegregate with the disorder and to be absent as common sequence polymorphisms, by studying 110 alleles, using DNA obtained from 65 unrelated normal individuals (20 males, 45 females).

Results

Analysis of a total of 84 RT-PCR products, ranging in size from 400–600 bp and encompassing the coding region of PHEX from the 11 unrelated XLH patients and 3 unrelated normal individuals, yielded 3 abnormally larger products involving the exons 7–11 region from 1 male patient from family R (Fig. 1Go). These 3 mutant RT-PCR products were approximately 470, 520, and 590 bp in size, compared with the wild-type (WT) 422-bp product obtained from normal individuals. DNA sequence analysis of these RT-PCR products confirmed that the WT product consisted of correctly spliced exons 7, 8, 9, 10, and 11 but that the mutant products contained insertions between the exon 7 and 8 sequences. These insertions were 51 bp, 100 bp, and 170 bp in size; and their respective RT-PCR products are referred to as m1, m2, and m3. Furthermore, the 51-bp insert, found in m1, the smallest of the mutant RT-PCR products (Fig. 1Go), was found in m2 and m3. Moreover, m3 contained the entire 100 bp of m2. A similar analysis of the patient’s affected daughter (II.1, Fig. 1Go) revealed the presence of WT and the 3 mutant RT-PCR products.



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  		Figure 1. Detection of abnormal RT-PCR products from the region encompassing exons 7–11. Three abnormally larger products (A) were found in one XLH patient, who is the affected father (I.1) from family R (Fig. 2Go). These three mutant products (m1, m2, and m3) were not detected in unrelated normal individuals (N1 and N2) who had only the expected WT product of approximately 420 bp. The patient’s affected daughter (II.1) has the WT and three mutant RT-PCR products. RT-PCR products were not obtained from the genomic control (G), thereby confirming the specificity of the primers [forward primer from exon 7 (nt 786–809) and reverse primer from exon 11 (nt 1209–1191)]. DNA size standard (S) markers, which were a 1-kb ladder, are indicated. DNA sequence analysis revealed that the WT product consisted of correctly spliced exons 7, 8, 9, 10, and 11 but that the mutant products had additional sequences inserted between exons 7 and 8 (B). Thus, the m1 product, which was 473 bp in size, contained a 51-bp insertion (black block) from nt +1216 to 1266 of intron 7; the m2 product, which was 522 bp in size, contained a 100-bp insertion (dark gray block) from nt +1167 to 1266 of intron 7; and the m3 product, which was 592 bp in size, contained a 170-bp insertion (stippled block), from nt +1097 to 1266, of which 100 bp were identical to those observed in m2. Further DNA sequence analysis revealed that the m1, m2, and m3 products were attributable to splicing and insertion of pseudoexons 7a, 7b, and 7c, respectively. These pseudoexons resulted from a combined use of the novel donor splice site (gtaagg) at position +1268 (arrow), which is caused by a mutation (Fig. 2Go), and 3 normally occurring, but redundant, acceptor splice sites (gcag or ccag) at nt + 1096, 1166, and 1215.

 
To determine the origins of these sequences that gave rise to m1, m2, and m3, a database search (National Centre for Biotechnology Information-Blast search) was carried out. This revealed that the inserted sequences originated from intron 7 of the PHEX gene. Thus, the 51 bp of m1 comprised nucleotides (nt) +1216 to +1266 of intron 7, the 100 bp of m2 comprised nt +1167 to +1266, and the 170 bp of m3 comprised nt +1097 to +1266 (Fig. 1Go). To determine the mechanisms that lead to these insertions, the DNA sequence of intron 7 in the proband was further analyzed. This revealed a mutation consisting of a g-to-t transversion at nt +1268 of intron 7 (Fig. 2Go). An examination of this sequence showed that the mutation had changed the WT ggaagg to a gtaagg, and hence a novel consensus donor splice site (20, 21). Indeed the gt dinucleotide represents the invariant bp found at all donor splice sites (20). The presence of this mutation (g to t) was confirmed by ASO hybridization analysis (Fig. 2Go). In addition, the mutation was shown to cosegregate with XLH in the family and not to be a common DNA sequence polymorphism.



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  		Figure 2. Detection of mutation in intron 7 in family R by ASO hybridization analysis. DNA sequence analysis of intron 7 in the XLH patient I.1 (arrowed), in whom 3 abnormal RT-PCR products were detected (Fig. 1Go), revealed a g->t transversion at nt +1268. An examination of the surrounding DNA sequence revealed that the WT sequence is ggaagg, whereas the mutant (m) sequence is gtaagg and, hence, a consensus donor splice site (A). Cosegregation of this novel consensus donor splice site with XLH in the family was demonstrated by ASO hybridization analysis (B). Furthermore, its absence from 110 alleles from 65 unrelated normal individuals (N1 to N3 shown) indicated that it is not a common polymorphism. Thus, 3 unrelated normal individuals (N1–N3) and the unaffected spouse (I.2) were found only to have the WT sequence and none of the m sequence. However, the affected father (I.1) is hemizygous for the m sequence, and his affected daughter (II.1) is heterozygous (WT/m). Individuals are represented as males (squares), females (circles), unaffected (open symbols), and affected (filled in symbols).

 
Usage of this novel donor splice site, together with the consensus acceptor splice site at exon 8 (Fig. 1Go), would explain the common origin and partially identical sequences of the mutant insertions but not their different sizes. To determine this, the intron 7 sequence was analyzed further for additional consensus acceptor splice sites. This revealed the occurrence of 3 naturally occurring consensus acceptor splice sites, gcag or ccag (20), that were located 51 bp, 100 bp, and 170 bp away in the 5' direction from the novel donor splice site (Fig. 1Go). Thus, use of the novel donor splice site (Fig. 2Go) and these 3 naturally occurring, but normally silent, acceptor splice sites would yield the 3 mutant products. These mutant transcripts (m1, m2, and m3) contain the pseudoexons 7a, 7b, and 7c, which (if translated) would result in the following PHEX proteins: m1 would yield an inframe insertion of 17 amino acids with an abnormally large PHEX protein of 766 amino acids; whereas m2 and m3 would yield frameshifts with truncated PHEX proteins after 11 and 10 missense amino acids, respectively. Thus, incorporation of these PHEX pseudoexons would result in a likely loss of function, and this is consistent with the predicted effects of the other PHEX mutations reported in XLH (7, 8, 9, 10, 11, 12, 13, 14, 15, 16). It is interesting to note that a WT PHEX transcript was not detected in the affected father (Fig. 1Go), thereby indicating a preferential usage of the novel donor splice site together with the alternative acceptor splice sites, as opposed to usage of the WT donor and acceptor splice sites. The occurrence of the WT and mutant transcripts (m1, m2, and m3) in the affected daughter likely resulted from use of the WT donor and acceptor splice sites, and the novel donor splice site and the 3 alternative naturally occurring acceptor splice sites, respectively.

The results of this study reveal that PHEX pseudoexons represent approximately 0.6% of all PHEX mutations but that, within the subgroup of XLH patients who do not harbor coding region mutations, they may represent up to 9% of mutations. The clinical features of this patient and his daughter from family R (Fig. 2Go), who both had the novel donor splice site leading to the incorporation of pseudoexons 7a, 7b, and 7c (Fig. 1Go), were similar to those observed in other XLH kindreds. Thus, the male patient (I.1, Fig. 2Go), whose mother was known to have XLH, had bone deformities and an adult height of 1.57m, which is below the 3rd centile and at the average height reported for 6 men with XLH who had received 1,25 (OH)2 vitamin D 3 treatment (22). Furthermore, the patient’s daughter (II.1, Fig. 2Go) had bowed legs and a height at age 11.7 yr that was below the 5th centile. In addition, her serum phosphate, whilst receiving no treatment, was 3.1 mg/dl, and this is similar to the average value of 3.0 ± 0.1 mg/dl observed in untreated prepubertal XLH girls (5).

Discussion

Our studies have identified PHEX pseudoexons in a family with XLH. Such PHEX pseudoexons have not been previously reported in XLH (7, 8, 9, 10, 11, 12, 13, 14, 15, 16); and indeed, pseudoexons as a cause of other diseases have only been reported on two (23, 24) other occasions. Thus, a pseudoexon of the ß-globin gene resulting from a mutation in intron two has been reported in ß-thalassemia (23), and two pseudoexons of the neurofibromatosis type 1 (NF1) gene resulting from a mutation in intron 30 have been reported in NF1 (24). The RNA splicing mechanisms involved in the occurrence of such pseudoexons in these diseases have been investigated (23, 24), and it has been proposed that the mutant sequence may compete with the normal sequence in forming base pairs with the small nuclear U1 RNA, which aligns both ends of an intron for cutting and splicing (25, 26). Indeed, the occurrences of mutant transcripts containing pseudoexons with reduced amounts of the WT transcript have been reported for the autosomal ß-globin and NF1 mutants (23, 24), thereby supporting this proposal. Furthermore, given that NF1 is a dosage-dependent disorder, it seems likely that the reduction in levels of normal mRNA transcripts that are associated with the pseudoexon transcripts is of significance in the etiology of the disease phenotype (24). The situation in the XLH patients (Fig. 1Go) is likely to be different because of X-chromosome inactivation (2, 11). The results from the affected father (I.1), who is observed to have only the mutant PHEX transcript, indicate a preferential usage of the novel donor splice site together with the alternative acceptor splice sites. The observed WT and mutant transcripts that were observed in the cells from the affected daughter (II.1), collectively, will be originating from her WT and mutant X-chromosome copies. Thus, the mutant pseudoexon transcripts will not be reducing the levels of normal PHEX transcript, because they are not present within the same cell.

Pseudoexons as disease-causing mutations are likely to be more common but remain under-recognized because the majority of studies concentrate on identifying mutations within coding regions and adjacent splice sites (7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). Indeed, of the 161 PHEX mutations reported to date in XLH patients, (7, 9, 10, 11, 12, 13, 14, 15, 16) all but 2 involve the coding region. One of these mutations is an a->g transition in the 5' UTR (12), and the other is described in the present study, which reports a g->t transversion within intron 7 that results in a novel donor splice site (Fig. 2Go). Use of this novel donor splice site with 3 naturally occurring, but normally unused, acceptor splice sites leads to the incorporation of 3 pseudoexons in the PHEX transcripts (Fig. 1Go). These PHEX pseudoexons, if translated, would result in either the inclusion of missense amino acids into the PHEX protein, or a truncated protein which would lack 5 of the 10 conserved cysteine residues and the pentapeptide zinc-binding motif, which is characteristic of such zinc metalloproteases (8). This would likely lead to a loss of activity. The function of PHEX remains to be elucidated, but PHEX does have a high degree of homology with the neutral endopeptidase (NEP) family members, including NEP, Kell antigen, endothelium converting enzymes (ECE-1 and ECE-2), endothelin-converting enzyme-like 1 (ECEL1, formerly known as XCE), and neprilysin-like peptide (NL1) (8, 27, 28, 29, 30, 31, 32, 33). NEP and endothelium-converting enzyme cleave peptide bonds and alter the activity of angiotensin and vasopressin and big endothelium, respectively (27, 28, 29), and it is postulated that PHEX may have a similar role. Indeed, immunofluorescence studies have revealed a cell-surface location for PHEX in an orientation that is similar to that for other NEPs and consistent with it being a type II integral membrane glycoprotein (34). A further functional analysis of PHEX and the effects of XLH mutations will be facilitated by the identification of the PHEX substrate, which is provisionally referred to as phosphatonin (17). PHEX mutations causing XLH are diverse in their types, and our studies identifying PHEX pseudoexons in XLH further expand the spectrum of these mutations. Our study reveals that in those XLH patients in whom coding-region PHEX mutations have not been found, a search for intronic mutations, e.g. by the RT-PCR method, is worthwhile, because they may represent approximately 9% of mutations in this group.

Footnotes

This work was supported by the Medical Research Council UK (to P.T.C., B.H., M.A.N., and R.V.T.) and Grant 8480 from The Shriners Hospitals for Children (to M.P.W.).

Abbreviations: ASO, Allele-specific oligonucleotide; HYP, hypophosphatemia; NEP, neutral endopeptidase; NF1, neurofibromatosis type 1; nt, nucleotide(s); UTR, untranslated region; WT, wild-type; XLH, X-linked hypophosphatemia.

Received January 29, 2001.

Accepted April 12, 2001.

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals