Clinical Endocrinology (1992) 37, 338-343

Genetic linkage studies of X-linked hypophosphataemic rickets in a Saudi Arabian family R. V. Thakker', M. R. Farmery', N. A. Sakatit and R. D. G. Miinert 'Division of Molecular Medicine, MRC Clinical Research Centre, Harrow, UK and TDepartrnent of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia (Received 13 February 1992; returned for revision 10 April 1992; finally revised 6 May 1992; accepted 19 May 1992)

Summary OBJECTIVE, PATIENTS AND DESIGN X-linked hypophos-

phataemic rickets (HYP) is the most common inherited form of rickets and the gene causing this disorder has been localized to Xp22.3-p21.3 by linkage studies of affected families of Northern European orlgln. In addition, the locus order Xpter-(DXS207-DXS43,DXSl97)-HYPDXS41-Xcen has been established and the flanking markers are useful for the presymptomatk dlagnosis of HYP. However, a recent study indicates locus heterogeneity and this may hinder the use of the flanking markers for presymptomatic diagnosis In additional families and in particular those from different populations. We have therefore investigatedone Saudi-Arabianfamily (13 affected and six unaffected members) with hypophosphataemic rickets for linkage to these and other X-linked markers. A total of 17 cloned human X chromosome sequences identifying restriction fragment length polymorphismswere used to localizethe mutant gene causing this disorder in the Saudi Arabian family. RESULTS Nine (four from Xp and five from Xq) of the 17 Xlinked DNA probes proved informative and linkage was established between HYP and the DSX41 locus, peak LOD score = 4.22 (recombinationfraction, 0 = 0.00).A positive peak LOD score of 2.32 (0=0.05) was also obtained between HYP and the DXS207 locus. Thus, the HYP gene In this Saudi Arablan family is linked to two of the four flanking markers which demonstrated linkage In famllles of Northern European origin. CONCLUSION We conclude that the X-linked hypophosphataemic rickets gene In a Saudi Arabian family Is Correspondence: Dr R. V. Thakker, MRC Molecular Medicine Grouo. Collier Building. Royal Postgraduate Medical school, DU Cane-Road, London w12 ONN, U i

338

located in the Xp22.3-p21.3, a region where this gene has previously been mapped by linkage studies of families of Northern European origin. Our studies have not demonstrated locus heterogeneity, so the flanking markers for HYP previously established in the families of NorthernEuropean origin will be useful In the genetic counselling and presymptomatic diagnosis of this disorder in the Saudi Arabian family.

Hypophosphataemic (vitamin D resistant) rickets is the commonest form of metabolic rickets in man (Thakker & O'Riordan, 1988) and is most frequently inherited as an Xlinked dominant trait (Winters et al., 1958; Graham et al., 1959; Burnett et al., 1964). The hypophosphataemic rickets gene (HYP) has been localized to the short arm of the Xchromosome in the region Xp22.31-p21.3 by linkage studies in 22 affected families of Northern European origin (Read et al., 1986; Machler et al., 1986; Thakker et al., 1987; Econs et al., 1991). In addition, the order of DNA markers around the HYP locus has been defined as Xpter-(DXS207,DXS43, DXS197)-HYP-DXS41-Xcen (Thakker et al., 1990) and these flanking markers (Fig. 1) are of use in the genetic counselling of some families. However, recent results from one British family indicate locus heterogeneity (Read et al., 1992) and it has been suggested that the X-linked hypophosphataemic rickets gene in this family may not be located in the region Xp22.31-p21.3. Such genetic heterogeneity, in which mutations at two or more genetic loci cause the same clinical phenotype, has been observed in autosomal dominant polycystic kidney disease (Romeo et al., 1988; Kimberling et al., 1988). Linkage between polycystic kidney disease and the a-globin locus on the short arm of chromosome 16 had previously been established in British and Dutch families (Reeders et al., 1985), but an analysis of one Italian (Romeo et af.,1988) and one Sicilian (Kimberling et al., 1988) family suffering from this renal disease revealed an absence of linkage to the a-globin locus. Thus, the previously established linked markers were not of use in the presymptomatic diagnosis and genetic counselling of these two families with polycystic kidney disease. We have sought for possible genetic heterogeneity of the X-linked hypophosphataemic rickets gene by investigating non-Northern European families and have performed linkage studies in a Saudi Arabian family suffering from hypophosphataemic rickets.

Clinical Endocrinology (1992) 37

Mapping hypophosphataemic rickets

339

Materlals and methods Patients

Probe r

P

Locus

\

782 / D2 pPA4B 199.6 c7 754 pOTC L1.28 M27P

-

I ’ U\

“c1

DXS85 DXS43 DXS207 DXS41 DXS28 DXS84 OTC DXS7 DXS255

pDp34

DXYSI

pYNH3

DXS287

p22-33 30Rlb

DXSII DXS37 DXS51 F9 DXS98 DXS52

Fig. 1 Map of some clinically useful DNA probes on the human X chromosome, which is schematically represented with Giemsa bands. The short arm is designated ‘p’ and the long arm is designated ‘q’. The DNA probes are cloned human X chromosome sequences and are shown juxtaposed to their region of origin. The region from which each DNA probe is derived is ascertained by in-situ hybridization, or by the use of somatic cell hybrids, or by linkage studies. Each DNA probe of unknown function is assigned a locus number; for example the DNA probe 99.6 is assigned DXS41. This indicates that DXS41 is a DNA sequence (D) from the X chromosome (X) detecting a single (S) DNA segment in the haploid genome, and is designated the number 41 by the Human Gene Mapping Committee (Kidd et ul., 1989). DNA probes of known function are allocated gene symbols; for example the genes encoding ornithine carbamoyl transferase and coagulation Factor IX are assigned OTC and F9, respectively. These DNA probes, which reveal RFLPs, have been used as genetic markers in linkage studies of families affected with X-linked hypophosphataemic rickets (HYP) and linkage to the Xp22.3-p21.3 loci (DXS207, DXS197, DXS43 and DXS41) has been previously established in families of Northern European origin (Thakker el af., 1990).

One Saudi Arabian kindred, designated SA/91 (Fig. 2) in whom hypophosphataemic rickets had occurred in four generations, was investigated. Serum urea, electrolytes, creatinine, calcium, phosphate, alkaline phosphatase activity and albumin were determined by a multi-channel autoanalyser, whilst individuals were not receiving treatment. Serum calcium was corrected to an albumin of 41 g/l, and the results are shown in Table 1. DNA hybridization analysis

Venous blood samples were collected in tubes containing EDTA and kept frozen at -70°C. Leucocyte DNA was prepared by standard methods (Kunkel et al., 1977)and 5 pg DNA was digested to completion with a fourfold excess of one of the following restriction enzymes: EcoRI, PvuII, XbaI, EcoRV, PstI, MspI or RsaI (Boehringer Mannheim, Lewes, East Sussex, UK or Pharmacia, Milton Keynes, Bucks, UK). The resulting fragments were separated by 0.80.9% agarose gel electrophoresis and transferred to a nylon membrane (Hybond-N, Amersham International, Aylesbury, Bucks, UK)by the method of Southern (1975). DNA probes were labelled by nick translation (Rigby et al., 1977) or by oligonucleotide primer synthesis (Feinberg 19Vogelstein, 1983) using d’P-dCTP. Seventeen cloned DNA probes from the X chromosome were used in the linkage studies (Fig. 1). Nine of the probes (782, D2, pPA4B, 99.6, C7, 754, pOTC, L1.28 and M27B) were from the short arm and 8 (pDp34, pYNH3, p22-33, 30RIb, 52A, FIX (Factor IX), 4D.8 and St14) were from the long arm of the X chromosome. These polymorphic probes define the loci DXS85, DXS43, DXS207, DXS41, DXS28, DXS84, OTC, DXS7, DXS255, DXYS 1, DXS287, DXSl 1, DXS37, DXS51, F9, DXS98 and DXS52 respectively (Fig. 1). Details of the probes and references are given by Kidd et al. (1989). The Southern blot was hybridized as described previously (Davies el al., 1983). Autoradiography with dual intensifying screens and preflashed Fuji medical X-ray films was performed at -70°C for 3-7 days to reveal the restriction fragment length polymorphisms (RFLPs). Linkage analysis

The numbers of cross-over events for recombinants that occurred between HYP and each DNA marker locus on the X chromosome were determined since these reflect the genetic distances between HYP and each marker locus. The ratio of recombinants to the total number of offspring is the

340

Clinical Endocrinology (1992) 37

R. V. Thakker et a/.

Family SA191 I

Locus DXS207 DXS255

1,2

II

III 1

2

3

4

5

6

7

8

9 1 0 1 1 1 2

I

Fig. 2 Pedigree of family SA/91, segregating for X-linked hypophosphataemicrickets and short arm RFLP loci, whose respective alleles and DXS255 (1,2,3,4). The loci are shown in the correct order but not are indicated in parentheses: DXS207 (Gg), DXS41 (Aa), DXS7 the correct distances apart. Individuals are represented as: 0,unaffected male; B, affected male; 0 , unaffected female; and 0 , affected

(a)

female. In some females, the inheritance of the paternal and maternal alleles can be ascertained, and in these the maternal X chromosome is shown on the right. Recombinants between HYP and each allele are indicated by an asterisk (*) and the centromere is shown by (*).

recombination fraction (O),whose value ranges from 0 to 0.5. A value of 0 indicates that the loci are very closely linked, while a value of 0.5 indicates that the loci are far apart or not linked. The probability that the two loci are linked is expressed as a ‘LOD score’, which is loglo of the odds ratio favouring linkage. A LOD score of +3, which indicates a probability in favour of linkage of 1000: 1, usually establishes linkage between two loci, and a LOD score of -2, indicating a probability against linkage of 100: 1, is taken to exclude linkage between two loci. The odds ratio favouring linkage is defined as the likelihood that the two loci are linked as a specified recombinant (0) versus the likelihood that the two loci are not linked (i.e. 0=0.5). LOD scores are evaluated over a range of 0,thereby enabling the genetic distance and maximum (or peak) probability favouring linkage between the two loci to be ascertained. The recombiat which the peak LOD score ( Z ( 6 ) )is nation value (8) obtained yields the best estimate of the genetic distance between the two loci. These calculations were performed using the computer programs MLINK and ILINK (Lathrop & Lalouel, 1984) from LINKAGE (version 4.7). The frequency of hypophosphataemic rickets was estimated to be and the RFLP allele frequencies used were previously

published values (Kidd et al., 1989). Varying the disease frequency had no effect on the results of the linkage analysis which utilized an X-linked dominant mode of inheritance. Results

The clinical, biochemical and radiological findings in 19 members of family SA/91 are summarized in Table 1. Thirteen patients (ten males, three females) suffered from hypophosphataemic rickets and six individuals (five males, one female) were unaffected. Aminoaciduria and glycosuria were not present. There was no history of a consanguineous marriage and the inheritance of the disease was compatible with that for an X-linked dominant disorder. Members of family SA/91 proved informative for nine Xlinked genetic markers, four from the short arm (Xp) and five from the long arm (Xq). The genotypes obtained with the use of the four informative markers (DXS207, DXS41, DXS7 and DXS255) from Xp in family SA/91 are shown in Fig. 2, and an analysis of recombination events helps to localize the HYP locus. There are no recombinants between HYP and DXS41 locus, though several recombinants occur with other markers. Subjects 11.2 and 11.5 are affected mothers who are

Mapping hypophosphataemic rickets

Clinical Endocrinology (1992) 37

341

Table 1 Clinical and biochemical findings

in members of family SA/9 I

Serum

Individual

Sex

11.2 11.4 11.5 111.1 111.2 111.3

F M F F M

111.4 111.5

111.6 111.7 111.8 111.9 111.10 111.11 111.12 111.13 111.16 111.17 IV. I Normal Adult Normal Child

M M M F M

M M M M M M M M M

Aget (years)

Rickets

Calcium (mmol/l)

Phosphate (mmol/l)

2.17 2.43 2.19 2.20 2.44 2.37 2.25 2.39 2.37 2.26 2.21 2.22 2.36 2.45 2.32 2.34 2.27 2.24 2.45

0.79 1.18 0.83

Y N Y N* Y N

A A A A A A 16 I4 I3 II 9 17

Y* N Y*

Y* Y* Y* Y* N Y* Y N Y Y*

15

13 10 22 16 14 cl

Alkaline phosphatase (iu/l)

1.10

0.63 1-39 0.77 1.66 0.93 0.78 0.80 0.79 0.92 1.83 0439 0.63 1.1 1 0.66 I .02

111 86 84 84 219 I03 828 368 683 608 379 575 473 288 556 1 I9 90 96 322

-

-

2.15-2'55

0.80-1.45

30-125

-

-

2.15-2.55

1.25-2.15

100-235

* Radiological changes of rickets. t A Adult (precise age unknown). All patients had normal creatinine. Y, Yes, N, No. Table 2 LOD scores for linkage of X-linked markers and hypophosphataemic rickets

LOD scores Z (0)

Peak Locus

Probe

DXS207 DXS41 DXS7 DXS255 DXYSI DXSl 1 DXS5 I F9 DXS52

pPA4B 99.6 L I .28 M27B PDP34 ~22-33 52A Factor IX St14

6

Z(6)

Z(O.001)

Z(0.05)

Z(O.10)

Z(0.15)

Z(0.20)

Z(0.30)

Z(0.40)

0.050

2.32 4.22 0.06 0.03

0.92 4.21 - 13.27 - 13.27 - 10.21 -7.67 - 12.36 -8.32 - 16.57

2.32 3.87 -3.31 -3.31 - 3.46 -2.61 -3.9 -2.69 - 4.84

2.3 1 3.51 -1.75 - 1.75 -2.30 - 1.14 -2.53 - 1.41 -2.92

2.16 3.12 -0.96 -0.97 - 1.64 - 1.25 - 1.75 -0.76 - 1.88

1.93 2.72 -0.48

1.35 1.84 -0.03 -0.06 -0.60 -0.47 -0.56 -0.04 -0.43

0.61 0.84 -0.06 0.03 -0.23 -0.18 -0.19 -0.01 -0.07

0.000 0400 0.400 0.500

0.500 0.500 0.500 0.500

0.00 0.00 0.00 0.00 0.00

heterozygous for DXS207, DXS41, DXS7 and DXS255. Their respective sons: 111.3 (unaffected), 111.4 (affected), and 111.10 (affected), 111.16 (unaffected) and 111.17 (affected), are recombinant for HYP and the proximal loci DXS7 and DXS255, but non-recombinant for the distal loci DXS207

-0.50 - 1.19 -0.9 1 - 1.22 -0.38 - 1.21

and DXS41. These results indicate that in this family the HYP locus is located distal to DXS7 and DXS255. However, the affected son 111.13 is recombinant for HYP and the distal locus DXS207 but non-recombinant for the proximal loci DXS41, DXS7 and DXS255, thereby locating the HYP locus

342

R. V . Thakker et al.

proximal to DXS207. The minimum number of total recombinants in this pedigree is therefore obtained by locating HYP between DXS207 and DXS7. In addition, segregation of the disease with the locus DXS4l was demonstrated in all 16 children of the affected mothers (11.2, 11.5 and 111.1) and the likelihood that these two loci are linked is shown in Table 2. Linkage between HYP and the DXS41 locus was established with a peak LOD score of 4.22, a recombination of 0.00, and a 95% confidence interval of 0.00fraction (0) 0.15. A positive LOD score of 2.32, 0 of 0.05, and a 95% confidence interval of 0.00-0.30 was also obtained between HYP and the DXS207 locus. All the other X-linked RFLP loci gave negative or low LOD scores. Linkage between HYP and DXS41 and DXS207 has previously been established in Northern European families (Thakker et al., 1990) and our results demonstrating linkage between HYP and these markers indicate that the gene involved in this disease in the two populations is likely to be the same. Discussion

Our linkage study of X-linked dominant hypophosphataemic rickets in the Saudi Arabian family represents the first such analysis in a nowEuropean population. In addition, our study of this Saudi Arabian family has established linkage between HYP and the locus DXS41 with a probability in favour of linkage > 16500: 1.Previous studies (Read et al., 1986; Machler et al., 1986; Thakker et al., 1987, 1990; Econs et al., 1991) in families of Northern European origin have established linkage between HYP and DXS41 and the combined observations indicate that locus heterogeneity of HYP between these two populations is unlikely. This finding is of importance as it will facilitate the use of the flanking markers, e.g. DXS41 and DXS207, for the genetic counselling and presymptomatic diagnosis of hypophosphataemic rickets in this Saudi Arabian family. However, the possibility that mutations in different genes which are linked to the DXS41 and DXS207 loci in the region Xp22.31-p21.3 may be responsible for the HYP phenotype in these two populations has not been excluded. For example, in the mouse the two X-linked dominant hypophosphataemic genes, hyp and gy are linked (Lyon et al., 1986) within one centiMorgan (0=0.01). The murine hyp gene is the homologue of HYP in man, but a human homologue for the murine gy mutation which is associated with a circling behaviour, an impairment in cochlear function, hypercalciuria, a raised serum 1,25dihydroxy vitamin D, concentration and hypophosphataemic rickets (Davidai et al., 1990) has not been established. Thus, phenotypic and genotypic heterogeneity have been reported for the mouse hypophosphataemic rickets genes

Clinical Endocrinology (1992) 37

and as genes that are X-linked in any one mammalian species are X-linked in all other mammals (Ohno, 1990) it would seem likely that human hypophosphataemic rickets may also be genetically and phenotypically heterogeneous. Clinical data do not strongly support the hypothesis of heterogeneity of X-linked dominant hypophosphataemic rickets. Although cases of hypophosphataemic rickets have been described that were due to autosomal recessive (Stamp & Baker, 1976; Perry & Stamp, 1978) or autosomal dominant (Harrison &Harrison, 1979; Scriver et al., 198I ) inheritance, or that had occurred in association with non-hereditary malformation complexes (Thakker et al., 1989), such cases can be distinguished from those of the X-linked dominant form on the basis of family history, biochemical abnormalities and age at diagnosis (Thakker & O’Riordan, 1988). Audiometric studies in patients with X-linked hypophosphataemic rickets have revealed sensorineural hearing deficits due to cochlear dysfunction (Boneh et al., 1987; Davies et al., 1984) and it has been proposed that this may represent the human homologue of the murine gy mutation, and thereby genetic heterogeneity. Such heterogeneity might also be detected by an analysis of families with differing racial origins. However, our comparative analysis of X-linked hypophosphataemic rickets in Saudi Arabian and European families does not provide evidence for different forms of Xlinked dominant hypophosphataemic rickets. Our findings are of clinical importance as they exclude heterogeneity and thereby enable the use of the currently available flanking genetic markers for genetic counselling and presymptomatic diagnosis of X-linked hypophosphataemic rickets in families from Saudi Arabia. Acknowledgements

We are grateful to the Medical Research Council (UK) for support; to Drs K. E. Davies, I. Craig and T. Kruse for the gift of probes; to the American Type Culture Collection (ATCC) and the Human Genome Mapping Project (MRC) for DNA probes; and to Mrs S. Kingsley for typing the manuscript . References

Boneh, A., Reade, T.M.,Scriver, C.R. & Rishikof, E. (1987) Audiometric evidence for two forms of X-linked hypophosphataemia in humans, apparent counterparts of Hyp and Gy mutations in mouse. American Journal of Medical Genetics, 27, 997-1 003. Burnett, C.H., Dent, C.E., Harper, C. & Warland, B.J. (1964) Vitamin D resistant rickets. Analysis of twenty-four pedigrees with hereditary and sporadic cases. American Journal of Medicine, 36,222-232.

Clinical Endocrinology (1992) 37

Davidai, G.A., Nesbitt, T. & Drezner, M.K. (1990) Normal regulation of calcitriol production in C y mice: Evidence for biochemical heterogeneity in the X-linked hypophosphataemic diseases. Journal of Clinical Investigation, 85, 334-339. Davies, K.E., Pearson, P.L., Harper, P.S., Murray, J.M., O’Brien, T., Sarfarazi, M. &Williamson, R. (1983) Linkage analysis of two cloned DNA sequences flanking the Duchenne muscular dystrophy locus on the short arm of the X chromosome. Nucleic Acids Research, 11,2302-23 12. Davies, M., Kane, R. & Valentine, J. (1984) Impaired hearing in X linked hypophosphataemic (vitamin D resistant) osteomalacia. Annals of Internal Medicine, 100, 230-232. Econs, M.J., Pericak-Vance, M.A., Betz, H., Bartlett, R.J., Speer, M.C. & Drezner, M.K. (1991) The human glycine receptor: a new probe that is linked to the X-linked hypophosphatemic rickets gene. Genomics, 7 , 4 3 9 4 1 . Feinberg, A.P. & Vogelstein, B. (1983) A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Analytical Biochemistry, 132,6- 13. Graham, J.B., McFalls, V.W. & Winters, R.W. (1959) Familial hypophosphataemia with vitamin D resistant rickets. I1 Three additional kindreds of the sex linked dominant type with a genetic analysis for four such families. American Journal of Human Genetics, 11, 31 1-332. Harrison, H.E. & Harrison, H.C. (1979) Disorders of calcium and phosphate metabolism in childhood and adolescence. Major Problems in Clinical Pediatrics, u), Rickets and Osteomolacia, 141-256. Kidd, K.K., Bowcock, A.M., Schmidtke, J.,Track, R.K., Ricciuti, F., Hutchings, G., Bale, A., Pearson, P. & Willard, H.F. (1989) Report of the DNA committee and catalogs of cloned and mapped genes and DNA polymorphisms. Cytogenetics and Cell Genetics, 51,622-947. Kimberling, W.J., Fain, P.R., Kenyon, J.B., Goldgar, D., Sujansky, E. & Gabow, P.A. (1988) Linkage heterogeneity of autosomal dominant polycystic kidney disease. New England Journal of Medicine, 319,913-918. Kunkel, L.M., Smith, K.D., Boyer, S.H., Borgaonker, D.S., Wachtel, S.S.,Miller, O.J., Breg, W.R., Jones, H.W. & Rary, J.M. (1977) Analysis of human Y chromosome specific reiterated DNA in chromosome variants. Proceedings ofthe National Academy of Sciences of the USA, 74, 1245-1249. Lathrop, G.M. & Lalouel, J.M. (1984) Easy calculation of LOD scores and genetic risks on small computers. American Journal of Human Genetics, 34,460465. Lyon, M.F., Scriver, C.R., Baker, L.R.I., Tenenhouse, H.S., Kronick, J. & Mandla, S.(1986) The Gy mutation: another cause of X linked hypophosphataemia in mouse. Proceedings of the National Academy of Sciences of the USA, 83,48994903. Machler, M., Frey, D., Gal, A., Orth, U., Wienker, T.F., Fanconi, A. & Schmid, W. (1986) X linked dominant hypophosphataemia is closely linked to DNA markers DXS41 and DXS43 at Xp22. Human Genetics, 73,271-275. Ohno, S.(1990) Sex Chromosomes and Sex Linked Genes. Springer, Berlin, Heidelberg, New York. Perry, W. & Stamp, T.C.B. (1978) Hereditary hypophosphataemic rickets with autosomal recessiveinheritance and severe osteosclerosis. Journal of Bone and Joint Surgery, 6OB, 430-434.

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Genetic linkage studies of X-linked hypophosphataemic rickets in a Saudi Arabian family.

OBJECTIVE, PATIENTS AND DESIGN: X-linked hypophosphataemic rickets (HYP) is the most common inherited form of rickets and the gene causing this disord...
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