J Korean Pediatr Soc.  1999 Jul;42(7):900-910.

Characterization of Molecular Defects in Korean Families with Inherited Ornithine Transcarbamylase Deficiency and Their Genotype-Phenotype Correlations

• Yoo HW

Abstract

PURPOSE: This study was undertaken to characterize molecular defects in Korean families with ornithine transcarbamylase(OTC) deficiency, correlate it with phenotype using in vitro expression study, and utilize it for making prenatal molecular diagnosis.
METHODS
To investigate molecular lesions resulting in OTC deficiency in 15 unrelated Korean families, the OTC genes of probands were amplified exon by exon and analyzed by direct sequencing of double stranded DNA. Based on their molecular lesions, prenatal monitoring of six fetuses at risk from four unrelated families was performed using genomic DNA from chorionic villi sampling(CVS). To analyze expression in vitro, mutant OTC cDNAs were constructed and cotransfected with beta-galactosidase gene into COS-1 cells by using lipofection. After transient expression, OTC activity was measured by colorimetric method.
RESULTS
Nine different mutations were identified in 10 out of 15 families ; six mutations were novel, involving well-conserved nucleotide sequences across species or CpG hot spot : T44I, M205T, H214Y, D249G, F281S, R320X. In vitro expression study revealed that the H214Y mutant showed a residual enzyme activity(13% vs 0% for D249G, 0% for R320X). However, clinical phenotype for H214Y was severe with neonatal onset. Three mutations were previously reported in other ethnic groups : R26Q, R141Q, R277W. Prenatal evaluation of 6 fetuses including one fraternal twins were successfully made. We predicted the outcome of all fetuses prenatally. They were also tested postnatally for the mutations to be unaffected.
CONCLUSION
The genotypes of Korean patients with OTC deficiency are genetically heterogeneous. Therefore, molecular diagnosis should be individualized in each family with OTC deficiency.

Keyword

Ornithine transcarbamylase(OTC) deficiency; Molecular defects; Genotype-phenotype; Expression; Prenatal diagnosis

MeSH Terms

Animals
Base Sequence
beta-Galactosidase
Chorionic Villi
COS Cells
Diagnosis
DNA
DNA, Complementary
Ethnic Groups
Exons
Fetus
Genetic Association Studies*
Genotype
Humans
Ornithine Carbamoyltransferase Deficiency Disease*
Ornithine Carbamoyltransferase*
Ornithine*
Phenotype
Prenatal Diagnosis
Twins, Dizygotic
DNA
DNA, Complementary
Ornithine
Ornithine Carbamoyltransferase
beta-Galactosidase