Homozygosity for uromodulin disorders: FJHN and MCKD-type 2

Rezende-Lima, Wânia; Parreira, Kleber Simônio; García-González, Miguel A.; Riveira, E.V.A.; Banet, Julio F.; Lens, Xosé M.

doi:10.1111/j.1523-1755.2004.00774.x

Cited by 56 publications

(25 citation statements)

References 25 publications

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“…Occurrence of homozygosity for a dominant UMOD mutation with more pronounced clinical symptoms was reported (27). Mutations can cause loss-ofphysiological function or gain-of-toxic function of the protein.…”

Section: Discussionmentioning

confidence: 97%

Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism

Kemter

Rathkolb

Rozman

et al. 2009

American Journal of Physiology-Renal Physiology

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Uromodulin-associated kidney disease is a heritable renal disease in humans caused by mutations in the uromodulin (UMOD) gene. The pathogenesis of the disease is mostly unknown. In this study, we describe a novel chemically induced mutant mouse line termed Umod(A227T) exhibiting impaired renal function. The A227T amino acid exchange may impair uromodulin trafficking, leading to dysfunction of thick ascending limb cells of Henle's loop of the kidney. As a consequence, homozygous mutant mice display azotemia, impaired urine concentration ability, reduced fractional excretion of uric acid, and a selective defect in concentrating urea. Osteopenia in mutant mice is presumably a result of chronic hypercalciuria. In addition, body composition, lipid, and energy metabolism are indirectly affected in heterozygous and homozygous mutant Umod(A227T) mice, manifesting in reduced body weight, fat mass, and metabolic rate as well as reduced blood cholesterol, triglycerides, and nonesterified fatty acids. In conclusion, Umod(A227T) might act as a gain-of-toxic-function mutation. Therefore, the Umod(A227T) mouse line provides novel insights into consequences of disturbed uromodulin excretion regarding renal dysfunction as well as bone, energy, and lipid metabolism.

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Section: Discussionmentioning

confidence: 97%

Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism

Kemter

Rathkolb

Rozman

et al. 2009

American Journal of Physiology-Renal Physiology

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show abstract

“…Since FJHN/MCKD2 represents an autosomal dominant disorder and most subjects are heterozygous with the homozygous patient being a rarity, 19) heterozygous Tg mice were used in this study. However, further investigation is needed using homozygous Tg mice because homozygous patients exhibit an earlier onset of hyperuricemia and renal insufficiency than heterozygous patients for the same mutation.…”

Section: Discussionmentioning

confidence: 99%

Progressive Accumulation of Intrinsic Mouse Uromodulin in the Kidneys of Transgenic Mice Harboring the Mutant Human Uromodulin Gene

Takiue

Hosoyamada

Yokoo

et al. 2008

Biological & Pharmaceutical Bulletin

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Familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease type 2 (MCKD2) are autosomal dominant disorders characterized by juvenile hyperuricemia of the underexcretion type, juvenile gout and chronic renal failure in the adult. FJHN/MCKD2 constitute diseases caused by mutations of the human uromodulin (UMOD) gene that encodes uromodulin, the most abundant glycoprotein in normal human urine. The mutations affect the transport of uromodulin, resulting in the accumulation of uromodulin in the kidneys of FJHN/MCKD2 patients. The purpose of this study was to confirm the accumulation of uromodulin in the kidneys of transgenic mice harboring the mutant human UMOD gene with mouse UMOD gene promoter, and to determine the relationship between its accumulation and the effect on uromodulin transport. The mutant human UMOD mRNA and its protein were expressed in the kidneys of transgenic mice. Moreover, the staining of human uromodulin was colocalized with that of mouse uromodulin. Although the human UMOD mRNA levels increased, the protein levels did not change and the accumulation of human uromodulin was not observed. However, the mouse uromodulin consists of two forms, 103 and 117 kDa, and the 103 kDa protein was gradually increased in the kidneys of transgenic mice. Human and mouse uromodulins in the kidneys of transgenic mice were mainly detected in the Triton X-100 insoluble microsomal fraction. Therefore, the progressive accumulation of uromodulin was observed in the plasma membrane of the kidneys of transgenic mice but the accumulated uromodulin protein was not that encoded by the transgene.

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“…This prediction turned out to be exactly the case. Rezende-Lima et al (50) showed in a family with familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease type II that homozygous carriers of C255Y had a much earlier onset of hyperuricemia and faster progression to end stage renal disease than the heterozygous carriers of the same mutation. By demonstrating a trapping effect of a mutated THP toward its wild-type counterpart, we are by no means excluding the global effects of the cytotoxicity of the mutant on the protein synthesis and trafficking in the host cells.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Cellular Effects of Tamm-Horsfall Protein Mutations and Their Rescue by Chemical Chaperones

Liu

El‐Achkar

et al. 2012

Journal of Biological Chemistry

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Background: Mutations of Tamm-Horsfall protein (THP) cause hereditary kidney diseases with unclear mechanisms. Results: Cysteine-altering THP mutants bind, trap, and reduce the apical release of wild-type THP, effects that can be ameliorated by various chemical chaperones. Conclusion: Intermolecular interactions between mutant and wild-type THP may affect disease phenotype. Significance: Chemical chaperones may be of therapeutic value in THP mutation-caused diseases.

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Homozygosity for uromodulin disorders: FJHN and MCKD-type 2

Abstract: The study shows that individuals with two UMOD mutations are viable, but they do have more severe disease on average than heterozygotes. This family sheds light on the possible disease mechanism in this disorder.

Cited by 56 publications

References 25 publications

Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism

Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism

Progressive Accumulation of Intrinsic Mouse Uromodulin in the Kidneys of Transgenic Mice Harboring the Mutant Human Uromodulin Gene

Molecular and Cellular Effects of Tamm-Horsfall Protein Mutations and Their Rescue by Chemical Chaperones

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