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Identification of missense, nonsense, and deletion mutations in the
GRHPR gene in patients with primary hyperoxaluria type II (PH2)
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Primary hyperoxaluria type II (PH2) is a rare disease
characterized by the absence of an enzyme with glyoxylate reductase,
hydroxypyruvate reductase, and D-glycerate dehydrogenase activities. The gene
encoding this enzyme (GRHPR) has been
characterized, and a single mutation has been detected in four PH2 patients.
In this report, we have identified five novel mutations. One nonsense
mutation (C295T) results in a premature stop codon at codon 99. A 4-bp
deletion mutation has been found in the 5' consensus splice site of intron D,
resulting in a predicted splicing error. Three missense mutations have been
detected, including a missense transversion (T965G) in exon 9 (Met322Arg), a
missense transition (G494A) in the putative co-factor binding site in exon 6
(Gly165Asp), and a substitution of an adenosine for a guanine in the 3' splice
site of intron G. The functional consequences of the missense transversion
and transition mutations have been investigated by transfection of cDNA
encoding the mutated protein into COS cells. Cells transfected with either
mutant construct have no enzymatic activity, a finding that is not
significantly different from the control (empty) vector (P<0.05).
These results further confirm that mutations in the GRHPR
gene form the genetic basis of PH2. Ten of the 11 patients that we have
genotyped are homozygous for one of the six mutations identified to date.
Because of this high proportion of homozygotes, we have used microsatellite
markers in close linkage with the GRHPR
gene to investigate the possibility that the patients are the offspring of
related individuals. Our data suggest that two thirds of our patients are the
offspring of either closely or distantly related persons. Furthermore,
genotyping has revealed the possible presence of a founder effect for the two
most common mutations and the location of the gene near the marker D9S1874.16"
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