ORIGINAL ARTICLE

Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy

T C Hart^1,2, M C Gorry¹, P S Hart², A S Woodard³, Z Shihabi⁴, J Sandhu⁵, B Shirts⁶, L Xu¹, H Zhu⁷, M M Barmada², A J Bleyer⁸

¹ University of Pittsburgh, School of Dental Medicine, Division of Oral Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
² Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
³ Bakersville Community Medical Clinic Inc, 86 N Mitchell Avenue, Bakersville, NC 28705, USA
⁴ Department of Pathology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA
⁵ Department of Urology, Cornell Medical School, New York, NY 10021, USA
⁶ University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA
⁷ Beijing Medical University, Beijing, China
⁸ Section on Nephrology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA

Correspondence to:
Correspondence to:
Dr T C Hart, Center for Craniofacial and Dental Genetics, University of Pittsburgh, School of Dental Medicine, 614 Salk Hall, Terrace Street, Pittsburgh, PA 15261, USA;
hart{at}sdmgenetics.pitt.edu

Introduction: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic.

Aim: To identify the gene and associated mutation(s) responsible for FJHN and MCKD2.

Methods: Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family).

Results: We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2.

Conclusion: These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.

Keywords: medullary cystic kidney disease 2; familial juvenile hyperuricaemic nephropathy; uromodulin; chromosome 16p; gout

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