Genetic Disorders – Development

Kidney International (2004) 66, 20–28; doi:10.1111/j.1523-1755.2004.00702.x

Mutant prenyltransferase-like mitochondrial protein (PLMP) and mitochondrial abnormalities in kd/kd mice

MIN PENG, LEONARD JARETT, RAY MEADE, MICHAEL P MADAIO, WAYNE W HANCOCK, ALFRED L GEORGE JR, ERIC G NEILSON and DAVID L GASSER

Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Department of Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania; Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Department of Medicine, Department of Cell and Developmental Biology, and Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee

Correspondence: David L. Gasser, Ph.D., Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia, PA 19104. E-mail: gasserd@mail.med.upenn.edu

Received 3 November 2003; Revised 16 December 2003; Re-revised 16 January 2004; Accepted 4 February 2004.

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Abstract

Mutant prenyltransferase-like mitochondrial protein (PLMP) and mitochondrial abnormalities in kd/kd mice.

Background

 

Mice that are homozygous for the kidney disease (kd) mutation are apparently healthy for the first 8 weeks of life, but spontaneously develop a severe form of interstitial nephritis that progresses to end-stage renal disease (ESRD) by 4 to 8 months of age. By testing for linkage to microsatellite markers, we previously localized the kd gene to a YAC/BAC contig.

Methods

 

The sequence of the entire critical region was examined, and candidate genes were identified. These candidate genes were sequenced in both mutant (kd/kd) mice and normal controls. The phenotype was further characterized by immunohistochemistry and electron microscopy. Transgenic mice were constructed that carried the wild-type allele of the prime candidate gene, and this transgene was transferred to a kd/kd background by breeding.

Results

 

We have obtained evidence that kd is a mutant allele of a novel gene for a prenyltransferase-like mitochondrial protein (PLMP). This gene is alternatively spliced, with the larger gene product having one domain that resembles transprenyltransferase and another that is similar to geranylgeranyl pyrophosphate synthase. The smaller gene product includes only the first domain. An antiserum to PLMP localizes to mitochondria, and ultrastructural defects are present in the mitochondria of renal tubular epithelial cells, and to a lesser extent, hepatocytes and heart cells from kd/kd mice. In a line of kd/kd mice that carried the wild-type PLMP allele as a transgene, only 1 out of 13 animals expressed the disease by 120 days of age.

Conclusion

 

The kd allele codes for a novel protein that localizes to the mitochondria, and the kd/kd mouse has dysmorphic mitochondria in the renal tubular epithelial cells. This mouse is therefore a unique animal model for studying mechanisms that lead to tubulointerstitial nephritis.

Keywords:

interstitial nephritis, kd gene, mitochondria

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