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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 464-470
Copyright © 2003 by The Endocrine Society

Original Article

Genetic Mapping Studies of Familial Juvenile Hyperuricemic Nephropathy on Chromosome 16p11-p13

Joanna M. Stacey, Jeremy J. O. Turner, Brian Harding, M. Andrew Nesbit, Peter Kotanko, Karl Lhotta, Juan G. Puig, Rosa J. Torres and Rajesh V. Thakker

Molecular Endocrinology Group, Nuffield Department of Medicine, Botnar Research Center, University of Oxford (J.M.S., J.J.O.T., B.H., M.A.N., R.V.T.), Oxford, United Kingdom OX3 7LD; Department of Internal Medicine, Krankenhaus der Barmherzigen Brueder (Teaching Hospital KFU, Graz) (P.K.), Graz, Austria A-8020; Department of Clinical Nephrology, Innsbruck University Hospital (K.L.), Innsbruck, Austria A-6020; and Servicio de Medicina Interna, Hospital General (J.G.P., R.J.T.), 28046 Madrid, Spain

Address all correspondence and requests for reprints to: Prof. R. V. Thakker, Molecular Endocrinology Group, Nuffield Department of Medicine, Botnar Research Center, University of Oxford, Nuffield Orthopedic Center, Headington, Oxford, United Kingdom OX3 7LD. E-mail: rajesh.thakker{at}ndm.ox.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Familial juvenile hyperuricemic nephropathy (FJHN), which is inherited as an autosomal dominant disorder, is characterized by hyperuricemia, a low fractional renal excretion of urate, and chronic renal failure that is associated with interstitial fibrosis. Studies in 4 families (3 European and 1 Japanese) have mapped the gene causing autosomal dominant FJHN to chromosome 16p11-p13. To refine this location we have pursued linkage studies in 7 European families with autosomal dominant FJHN and used 11 chromosome 16p11-p13 polymorphic loci whose order has been established as 16pter-D16S3069-D16S3060-D16S3041-D16S3036-D16S3046-[D16S403,D16S417]-D16S420-D16S3113-D16S401-D16S3133-16cen. Cosegregation between these polymorphic loci and FJHN was observed in 5 of the families, and linkage was established between FJHN and 6 loci (peak LOD score, 5.32 with D16S417, at 0% recombination), with the most likely location of FJHN being within a 22-centimorgan interval flanked centromerically by D16S401 and telomerically by D16S3069. Furthermore, FJHN in 2 families was found not to be linked to chromosome 16p11-p13, thereby demonstrating genetic heterogeneity. Thus, 5 additional families with FJHN showing linkage to chromosome 16p11-p13 loci have been identified, and genetic heterogeneity has been demonstrated in more than 25% of FJHN families. These results will facilitate the characterization of this gene regulating urate metabolism.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
FAMILIAL JUVENILE hyperuricemic nephropathy (FJHN; OMIM 162000), which is also referred to as familial juvenile gouty nephropathy, is an autosomal dominant disorder characterized by hyperuricemia, a low fractional renal urate excretion, interstitial nephropathy with basement membrane thickening and glomerulosclerosis (Fig. 1Go), and chronic renal failure (1). The first manifestation of FJHN is usually renal urate hypoexcretion, and this generally occurs around the second or third decade of life (2, 3). The hyperuricemia, which may or may not be associated with gouty arthritis, can be controlled with xanthine oxidase inhibitors (4, 5) or uricosuric drugs (6), and this may retard the progression of renal failure in some patients (7). The gene causing FJHN has been mapped to chromosome 16p11-p13 (8, 9, 10) and in close proximity to the gene for medullary cystic kidney disease type 2 (MCKD2, OMIM 603860), which has many clinical similarities to FJHN. For example, patients with MCKD2 may also suffer from hyperuricemia commencing in the second and third decades of life that is associated with gout and a progression to end-stage renal failure due to tubulointerstitial fibrosis and basement membrane thickening (11). Furthermore, some patients with FJHN have been reported to have medullary cysts that are similar to those in patients with MCKD2 (8). However, there are important differences between MCKD2 and FJHN, and patients with MCKD2 have a reduced urine-concentrating ability and salt wasting that has not been observed in patients with FJHN (11). Thus, it may be that FJHN and MCKD2 are allelic variants of one gene, or else their etiology may involve two different genes. Furthermore, both FJHN and MCKD are genetically heterogeneous disorders. Thus, linkage to chromosome 16p11-p13 loci has been excluded in one family with autosomal dominant FJHN (10), and autosomal dominant MCKD type 1 (MCKD1; OMIM 174000) has been mapped to chromosome 1q21 (12). To further refine the map location of FJHN and assess the frequency of genetic heterogeneity, we have ascertained seven families and performed linkage studies using polymorphic loci from chromosome 16p11-p13.



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  		Figure 1. Histology of renal biopsy, stained with hematoxylin and eosin, from the affected individual II.1 of kindred 13/00 (see Fig. 2Go). Mild tubulointerstitial nephropathy with areas of interstitial fibrosis (indicated by arrows) is observed. Note that of the three glomeruli, one is completely sclerosed (A), another (B) shows marked fibrosis of Bowman’s capsule, and one (C) is normal.

 

   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and families

Seven kindreds (3 from Austria and 4 from Spain) with autosomal dominant FJHN (Fig. 2Go) were ascertained. The clinical and biochemical findings in the 3 kindreds from Austria (11/00, 16/00, and 13/00) and 3 kindreds from Spain (1/96, 13/96, and 20/96) have been previously reported (13, 14, 15). Kindred 12/96 (Fig. 2Go) from Spain, which has not been previously reported, had similar clinical and biochemical findings (details available on request). Venous blood samples for genetic studies were obtained after informed verbal consent was given, as approved by the local ethical committee guidelines, from 58 family members (28 affected, 18 unaffected, and 12 unaffected spouses).



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  		Figure 2. Kindreds with autosomal dominant FJHN. Three kindreds (11/00, 13/00, and 16/00) are from Austria (13 14 ) and four kindreds (1/96, 20/96, 13/96 and 12/96) are from Spain (15 ). Squares indicate males, and circles indicate females. Unblackened symbols indicate unaffected individuals, and blackened symbols indicate affected individuals. Deceased individuals are shown by diagonal bars across the square or circle. A black dot in the center of the symbol denotes carrier status, and an asterisk indicates an individual from whom a blood sample was not available.

 
Genetic markers

Leukocyte DNA was prepared from venous blood samples and was used to detect polymorphisms in microsatellite tandem repeats, as previously described (16, 17). Eleven polymorphic loci from chromosome 16p11-p13 whose order from the Marshfield Genetic and Ensembl Physical Maps has been established as 16pter-D16S3069-D16S3060-D16S3041-D16S3036-D16S3046-[D16S403,D16S417]-D16S420-D16S3113-D16S401-D16S3133-16cen, were used. The location of D16S403, however, is not certain, and we have placed it adjacent to D16S417, which is in agreement with the Marshfield and Cedar Genetics Maps. Fluorescently labeled primers were used for the loci, with the exception of D16S3133, D16S401, and D16S3041 for which radioactively ([{gamma}-32P]ATP) end-labeled primers were used as previously described (18).

Linkage analysis

Conventional two-point LOD scores were calculated using the LINKAGE computer programs (16, 17, 19), with the frequency and penetrance of FJHN set at 10-4 and 95%, respectively. Varying the disease or allele frequencies or the penetrance value had no significant effect on the results of linkage analysis. Individual II.4 from family 1/96 (Fig. 2Go), who is unaffected but has an affected son (III.2), was entered as unaffected for the linkage analysis.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The 11 polymorphic loci, whose consensus order on chromosome 16p11-p13 has been established as 16pter-D16S3069-D16S3060-D16S3041-D16S3036-D16S3046-[D16S403,D16S417]-D16S420-D16S3113-D16S401-D16S3133-16cen, proved to be informative in the 7 FJHN kindreds. An examination of the haplotypes revealed cosegregation with FJHN in five (11/00, 13/00, 1/96, 20/96 and 13/96) of the seven families, and in the remaining two families (12/96 and 16/00) affected individuals were observed with different haplotypes, thereby indicating an absence of cosegregation. These 2 families (12/96 and 16/00), who had clinical and biochemical features of FJHN that were indistinguishable from those of the other 5 FJHN kindreds, were not included in further linkage analysis. Linkage between FJHN and 6 of the 11 polymorphic loci (Table 1Go) from chromosome 16p11-p13 was established in the 5 FJHN families (11/00, 13/00, 1/96, 20/96, and 13/96), with the highest LOD score of +5.32 at 0% recombination being observed between D16S417 and FJHN. These results confirm the previous localization of FJHN to this region (8, 9, 10). Analysis of individual recombinants helped to refine the region containing the FJHN locus, as illustrated by an examination of the haplotypes obtained at the 11 chromosome 16p11-p13 loci in kindred 11/00 (Fig. 3Go), which consisted of 32 individuals (27 surviving and 5 deceased) from 4 generations. FJHN is cosegregating with the haplotype [1, 4, 1, 1, 4, 2, 6, 4, 1, 4, 3] defined by the loci D16S3069, D16S3060, D16S3041, D16S3036, D16S3046, D16S403, D16S417, D16S420, D16S3113, D16S401, and D16S3133, respectively, in affected individuals II.2, II.11, III.1, III.4, and III.14. However, affected individual III.6 has inherited a recombinant haplotype that locates FJHN telomeric to D16S401, and this recombinant is also inherited by his affected son, IV.1. Affected individual II.8 has inherited another recombinant haplotype that locates FJHN centromeric to D16S3069. The combined observations of the recombinants in affected individuals II.8, III.6, and IV.1 locate FJHN within 22 centimorgans (cM), which is equivalent to 12 megabases (Mb) on the physical map (UDB), an interval flanked centromerically by D16S401 and telomerically by D16S3069. An examination of the haplotypes at these 11 loci in the other 4 kindreds (20/96, 1/96, 13/96, and 13/00; Fig. 2Go) did not reveal the presence of such recombinants, but showed cosegregation between each locus and FJHN. Furthermore, nonpenetrance for FJHN was also identified. Thus, individual II.4 from kindred 1/96 (Fig. 2Go), who is an unaffected mother in her sixth decade of life with a serum creatinine of 0.8 mg/dl (normal, <1.5 mg/dl) and a serum uric acid of 4.6 mg/dl (normal, <5.25 mg/dl) and has an affected son (III.2) aged 27 yr, was found to have the same haplotype as her affected sister (II.2), niece (III.1), and son (III.2). It is important to recognize such nonpenetrance, which is common for autosomal dominant disorders (20), because it may confound the analysis of linkage studies. Similarly, it is important to recognize genetic heterogeneity, which was found in more than 25% of our FJHN families, as this may also confound such linkage studies.


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  		Table 1. Two-point linkage analysis between FJHN and 11 loci from chromosome 16p11-13

 


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  		Figure 3. Pedigree of kindred 11/00 segregating for FJHN and chromosome 16p11-p13 loci. The paternal haplotypes are on the left, and the maternal haplotypes are on the right. Deduced haplotypes are within square brackets. The symbols denoting individuals are described in Fig. 2Go. FJHN is segregating with the haplotype [1, 4, 1, 1, 4, 2, 6, 4, 1, 4, 3], defined by the loci listed below individual I.1 (e.g. in the five affected individuals II.2, II.11, III.1, III.4, and III.14). Blackened bars indicate affected haplotypes, and unblackened bars indicate unaffected haplotypes. Recombinants between FJHN and the centromeric loci D16S401 and D16S3133 were observed in affected individuals II.5, III.6, and IV.1. Affected individual II.8 revealed a recombinant between the telomeric locus D16S3069 and FJHN, and unaffected individual III.2 revealed recombinants between the telomeric loci D16S3069 and D16S3060. However, recombinants in unaffected individuals require cautious interpretation, as nonpenetrance of FJHN has been observed (e.g. in family 1/96), and to minimize errors that may arise from an incorrect assignment of the phenotype, we elected to use only those recombinants that were observed in affected individuals for defining the critical interval for FJHN. Thus, the observations of recombinants in the affected individuals locate FJHN in the 22-cM interval between D16S3069 and D16S401.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our study localizing the FJHN locus to a 22-cM interval, which is equivalent to 12 Mb on a physical map between D16S3069 and D16S401 (Fig. 4Go) on chromosome 16p12-p13, reveals 4 important aspects in the search for this gene regulating uric acid metabolism. First, it identifies 5 additional families that have FJHN linked to chromosome 16p11-p13, thereby bringing the total number of such reported kindreds to 9 (8, 9, 10). Second, it further establishes genetic heterogeneity for FJHN in more than 25% of families, by showing a lack of cosegregation between FJHN and the chromosome 16p11-p13 loci in two families (12/96 and 16/00), which has previously been reported in only 1 family (10). Such genetic heterogeneity has also been established for MCKD, which has marked similarities in its genetic map location (Fig. 4Go) and clinical features to FJHN. These similarities are highlighted by 3 affected members of the Belgian FJHN kindred, who had renal medullary cysts that were indistinguishable from those observed in MCKD2, and it is of importance to note that approximately one third of MCKD kindreds will have members with hyperuricemia (11, 21, 22, 23). These observations suggest the intriguing possibility that FJHN in some kindreds who do not show linkage to chromosome 16p11-p13 may be linked to chromosome 1q21, which is the location of MCKD1. Our identification of 2 FJHN families, 12/96 and 16/00, which by themselves are not large enough to establish this, may help in future studies to explore this hypothesis. Third, it reveals nonpenetrance of FJHN (family 1/96) in a 59-yr-old woman and suggests that other genetic or environmental factors may potentially influence the phenotypic expression of the mutation, and that mapping data based on recombinants in unaffected individuals should be interpreted with caution. Fourth, it indicates that the interval containing FJHN, which is flanked by D16S3069 and D16S401, is still large and consists of approximately 22 cM, which is equivalent to 12 Mb, and contains approximately 400 genes (Ensembl database), none of which is a known urate transporter. This finding is in broad agreement with the 3 previous reports from studies of Czech (10), Belgian (8), and Japanese (9) FJHN families (Fig. 4Go). Thus, FJHN in the two Czech families was located to a 12-cM region flanked by D16S499 and D16S3113 (10), to a 14-cM region flanked by D16S3069 and D16S3036 in 1 Belgium family (8), and to a 7-cM region flanked by D16S412 and D16S3116 in 1 Japanese family (9). However, attempts to further narrow the interval containing FJHN by combining data from all of these studies requires caution, as there are important differences. For example, the intervals defined by the Belgium and Japanese families are mutually exclusive, although they both overlap with the intervals defined by the Czech, Austrian, and Spanish families. The results from the Belgium and Japanese families may either be due to the involvement of two different FJHN genes residing on 16p or, alternatively, to differences in the order of loci used from constructed maps. Indeed, the latter possibility may have particular relevance as the exact location of D16S403, which is 1 of the telomeric flanking loci in the Japanese kindred (9), has been unclear. Thus, in the GeneMap 99 RH map, D16S403 was located between D16S417 and D16S420, but the most recent edition of the Ensembl database has repositioned D16S403 more telomeric between D16S501 and D16S3046, whereas 3 other genetic and physical maps (UDB, Cedar Genetics, and Marshfield) locate D16S403 within the 3- to 5-cM region between D16S420 and D16S3036. This uncertainty regarding the location of D16S403 makes it difficult to use these data for delineating the telomeric boundary for the FJHN region in the Japanese kindred. However, a recombinant between FJHN and D16S412 was reported in an affected individual from the Japanese kindred, and as the location of D16S412 is better defined, this helps to delineate the likely telomeric boundary for FJHN in the Japanese kindred. These findings suggest the possibility that there may be two distinct FJHN loci on chromosome 16p (Fig. 4Go), and this is supported by the following two observations. An analysis of 11.8 Mb of genome sequence from chromosome 16p13.2-p11.2 has revealed the presence of highly homologous, evolutionary recently duplicated tracts of sequence in 16p (24). These duplications have important implications for mapping and gene analysis and may contribute to the occurrence of 2 distinct FJHN loci. Indeed, 2 different genes encoding the subunits of the amiloride-sensitive epithelial sodium channel located on chromosome 16p12.1 are known to cause Liddle’s syndrome (25), which is a form of salt-sensitive hypertension. Thus, mutations of both the ß- (26) and {gamma}-subunits of the epithelial sodium channel (25) result in Liddle’s syndrome of indistinguishable phenotypes. Furthermore, more than two distinct chromosome 16 loci have been reported for familial infantile convulsions (27), thereby further supporting the observations of highly homologous duplicated genomic sequences in this region. Our identification of 5 additional FJHN families that establish linkage of this disease to chromosome 16p11-p13 will help to explore further these possibilities and to elucidate the gene causing this disorder of uric acid metabolism.



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  		Figure 4. Map locations on chromosome 16p11-p13 of FJHN reported by four studies. A schematic representation of chromosome 16 is shown on the left together with the location of some disease loci, e.g. Liddle’s syndrome, which is due to mutations of the ß- and {gamma}-subunits of ENAC, and forms of familial infantile convulsions (27 ) (shaded bar). The 26-cM interval containing the reported (8 9 10 ) locations of FJHN is shown by the enlarged map on the right. The consensus locus order was derived from the two genetic maps (Marshfield and Cedar Genetics) and the two physical maps (Ensembl and UDB) and is shown with the genetic (centimorgans) distance. The location of D16S403, which varies among these maps, is shown with the square bracket denoting the region that encompasses its likely location. The locations of FJHN reported by studies of Czech (a) (10 ), Japanese (b) (9 ), Belgian (c) (8 ), and Austrian and Spanish (d) (present study) kindreds is shown. The location of MCKD2 (28 29 ) is shown between the arrowheads.

 


   Acknowledgments
 
We thank the United Kingdom Medical Research Council, Human Genome Mapping Project, for computing facilities. Electronic database information: URLs for data in this article are as follows: 1) National Center for Biotechnology Information, http://www.ncbi.nlm.nih.gov; 2) The Sanger Center and European Bioinformatics Institute, http://www.ensembl.org; 3) UK Human Genome Mapping Project Resource Center, http://www.hgmp.mrc.ac.uk; 4) Cedar Genetics, http://www.cedar.genetics.soton.ac.uk/ldb/chrom16/map.html; 5) Integrated Unified Database, http://bioinformatics.weizmann.ac.il/cgi-bin/udb/search_map_sbr.pl; 6) Marshfield Genetic Map, http://www.marshfieldclinic.org/research/genetics/physical_maps/chromosome16.htm; and 7) Genemap99, http://www.ncbi.nlm.nih.gov/genemap/.


   Footnotes
 
This work was supported by the United Kingdom Medical Research Council (to J.M.S., J.J.O.T., B.H., M.A.N., and R.V.T.).

J.M.S. and J.J.O.T. contributed equally to this work.

J.J.O.T. is a Medical Research Council training fellow.

Abbreviations: FJHN, Familial juvenile hyperuricemic nephropathy; MCKD1, medullary cystic kidney disease type 1.

Received August 13, 2002.

Accepted October 1, 2002.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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