Mice with adenine phosphoribosyltransferase deficiency develop fatal 2,8-dihydroxyadenine lithiasis

Nicola J. Redhead, Jim Selfridge, Chao-Liang Wu, David W. Melton

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Deficiencies in different steps of purine metabolism give rise to a number of human inherited disorders. Lesch-Nyhan syndrome is a severe neurological disorder, caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). HPRT-deficient mice have been generated, but have proved to be an unsuccessful model of the human disease. We have suggested that this may be due to a greater dependency in rodents on the other purine salvage enzyme, adenine phosphoribosyltransferase (APRT). We have generated an APRT-deficient mouse line by gene targeting, with a phenotype that closely resembled the symptoms of APRT deficiency in man. APRT null mice were viable, but 90% died prematurely before 6 months of age, displaying highly abnormal kidney morphology, with pathology characteristic of tubule obstruction. These mice have elevated urinary levels of adenine and 2,8-dihydroxyadenine, a highly insoluble adenine derivative, plus birefringent crystalline deposits and calculi within tubules throughout the kidney. A standard therapy for APRT-deficient human patients is the administration of the xanthine oxidase inhibitor, allopurinol. This has proved an effective therapy for APRT null mice, preventing accumulation of 2,8-dihydroxyadenine and much of the resultant renal obstruction, allowing us to establish a breeding line. We believe that these mice should provide a useful model for further study of APRT deficiency in humans. Furthermore, by generating APRT and HPRT double mutants, we will be able to test our hypothesis that both genes must be inactivated in mice before a model for Lesch-Nyhan syndrome can be obtained.

Original languageEnglish
Pages (from-to)1491-1502
Number of pages12
JournalHuman Gene Therapy
Volume7
Issue number13
DOIs
Publication statusPublished - 1996 Aug 20

Fingerprint

Adenine Phosphoribosyltransferase
Lithiasis
Hypoxanthine Phosphoribosyltransferase
Lesch-Nyhan Syndrome
Adenine
Kidney Tubules
Kidney
Allopurinol
Gene Targeting
Xanthine Oxidase
Calculi
Enzymes
2,8-dihydroxyadenine
Adenine phosphoribosyltransferase deficiency
Nervous System Diseases
Breeding
Rodentia
Pathology
Phenotype
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Redhead, Nicola J. ; Selfridge, Jim ; Wu, Chao-Liang ; Melton, David W. / Mice with adenine phosphoribosyltransferase deficiency develop fatal 2,8-dihydroxyadenine lithiasis. In: Human Gene Therapy. 1996 ; Vol. 7, No. 13. pp. 1491-1502.
@article{5324079b36cf444cb2fac1ff24c8e2be,
title = "Mice with adenine phosphoribosyltransferase deficiency develop fatal 2,8-dihydroxyadenine lithiasis",
abstract = "Deficiencies in different steps of purine metabolism give rise to a number of human inherited disorders. Lesch-Nyhan syndrome is a severe neurological disorder, caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). HPRT-deficient mice have been generated, but have proved to be an unsuccessful model of the human disease. We have suggested that this may be due to a greater dependency in rodents on the other purine salvage enzyme, adenine phosphoribosyltransferase (APRT). We have generated an APRT-deficient mouse line by gene targeting, with a phenotype that closely resembled the symptoms of APRT deficiency in man. APRT null mice were viable, but 90{\%} died prematurely before 6 months of age, displaying highly abnormal kidney morphology, with pathology characteristic of tubule obstruction. These mice have elevated urinary levels of adenine and 2,8-dihydroxyadenine, a highly insoluble adenine derivative, plus birefringent crystalline deposits and calculi within tubules throughout the kidney. A standard therapy for APRT-deficient human patients is the administration of the xanthine oxidase inhibitor, allopurinol. This has proved an effective therapy for APRT null mice, preventing accumulation of 2,8-dihydroxyadenine and much of the resultant renal obstruction, allowing us to establish a breeding line. We believe that these mice should provide a useful model for further study of APRT deficiency in humans. Furthermore, by generating APRT and HPRT double mutants, we will be able to test our hypothesis that both genes must be inactivated in mice before a model for Lesch-Nyhan syndrome can be obtained.",
author = "Redhead, {Nicola J.} and Jim Selfridge and Chao-Liang Wu and Melton, {David W.}",
year = "1996",
month = "8",
day = "20",
doi = "10.1089/hum.1996.7.13-1491",
language = "English",
volume = "7",
pages = "1491--1502",
journal = "Human Gene Therapy",
issn = "1043-0342",
publisher = "Mary Ann Liebert Inc.",
number = "13",

}

Mice with adenine phosphoribosyltransferase deficiency develop fatal 2,8-dihydroxyadenine lithiasis. / Redhead, Nicola J.; Selfridge, Jim; Wu, Chao-Liang; Melton, David W.

In: Human Gene Therapy, Vol. 7, No. 13, 20.08.1996, p. 1491-1502.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mice with adenine phosphoribosyltransferase deficiency develop fatal 2,8-dihydroxyadenine lithiasis

AU - Redhead, Nicola J.

AU - Selfridge, Jim

AU - Wu, Chao-Liang

AU - Melton, David W.

PY - 1996/8/20

Y1 - 1996/8/20

N2 - Deficiencies in different steps of purine metabolism give rise to a number of human inherited disorders. Lesch-Nyhan syndrome is a severe neurological disorder, caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). HPRT-deficient mice have been generated, but have proved to be an unsuccessful model of the human disease. We have suggested that this may be due to a greater dependency in rodents on the other purine salvage enzyme, adenine phosphoribosyltransferase (APRT). We have generated an APRT-deficient mouse line by gene targeting, with a phenotype that closely resembled the symptoms of APRT deficiency in man. APRT null mice were viable, but 90% died prematurely before 6 months of age, displaying highly abnormal kidney morphology, with pathology characteristic of tubule obstruction. These mice have elevated urinary levels of adenine and 2,8-dihydroxyadenine, a highly insoluble adenine derivative, plus birefringent crystalline deposits and calculi within tubules throughout the kidney. A standard therapy for APRT-deficient human patients is the administration of the xanthine oxidase inhibitor, allopurinol. This has proved an effective therapy for APRT null mice, preventing accumulation of 2,8-dihydroxyadenine and much of the resultant renal obstruction, allowing us to establish a breeding line. We believe that these mice should provide a useful model for further study of APRT deficiency in humans. Furthermore, by generating APRT and HPRT double mutants, we will be able to test our hypothesis that both genes must be inactivated in mice before a model for Lesch-Nyhan syndrome can be obtained.

AB - Deficiencies in different steps of purine metabolism give rise to a number of human inherited disorders. Lesch-Nyhan syndrome is a severe neurological disorder, caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). HPRT-deficient mice have been generated, but have proved to be an unsuccessful model of the human disease. We have suggested that this may be due to a greater dependency in rodents on the other purine salvage enzyme, adenine phosphoribosyltransferase (APRT). We have generated an APRT-deficient mouse line by gene targeting, with a phenotype that closely resembled the symptoms of APRT deficiency in man. APRT null mice were viable, but 90% died prematurely before 6 months of age, displaying highly abnormal kidney morphology, with pathology characteristic of tubule obstruction. These mice have elevated urinary levels of adenine and 2,8-dihydroxyadenine, a highly insoluble adenine derivative, plus birefringent crystalline deposits and calculi within tubules throughout the kidney. A standard therapy for APRT-deficient human patients is the administration of the xanthine oxidase inhibitor, allopurinol. This has proved an effective therapy for APRT null mice, preventing accumulation of 2,8-dihydroxyadenine and much of the resultant renal obstruction, allowing us to establish a breeding line. We believe that these mice should provide a useful model for further study of APRT deficiency in humans. Furthermore, by generating APRT and HPRT double mutants, we will be able to test our hypothesis that both genes must be inactivated in mice before a model for Lesch-Nyhan syndrome can be obtained.

UR - http://www.scopus.com/inward/record.url?scp=0029763372&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029763372&partnerID=8YFLogxK

U2 - 10.1089/hum.1996.7.13-1491

DO - 10.1089/hum.1996.7.13-1491

M3 - Article

C2 - 8864750

AN - SCOPUS:0029763372

VL - 7

SP - 1491

EP - 1502

JO - Human Gene Therapy

JF - Human Gene Therapy

SN - 1043-0342

IS - 13

ER -