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.


CONCLUSIONS
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.
Peng
Min
M
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Jarett
Leonard
L
Meade
Ray
R
Madaio
Michael P
MP
Hancock
Wayne W
WW
George
Alfred L
AL
Neilson
Eric G
EG
Gasser
David L
DL
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D022202:Chromosomes, Artificial, Bacterial; D004122:Dimethylallyltranstransferase / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000648:ultrastructure; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D014018:Tissue Distribution
D024101:Mitochondrial Proteins; D004122:Dimethylallyltranstransferase; C494606:PLMP protein, mouse