Paternal transmission and slow elimination of mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients.
In ten families with late-onset ornithine transcarbamylase (OTC) deficiency in male patients, three mutant alleles-R40H, R277W, and Y55D-were identified. In a total of 20 informative parent-offspring pairs, father-to-daughter transmission and mother-to-offspring transmission occurred in five (25%) and 15 (75%), respectively, indicating that paternal transmission contributes substantially to the pool of these mutant alleles. Relative reproductive fitness of males and females carrying the mutant alleles was calculated to be 0.49 and 0.89, respectively. Comparison of the life span of the mutant alleles, estimated on the basis of these fitness values with those associated with classic phenotype (neonatal onset) in which reproductive fitness of male patients was nil, revealed that mutant alleles associated with the late-onset phenotype were eliminated more slowly. This would allow the late-onset phenotype mutant alleles to be retained more frequently in a population than those associated with classic phenotype. Although heterozygous females carrying the late-onset phenotype mutant alleles were generally asymptomatic, one female carrying the R40H allele died after a hyperammonemic episode at the age of 18 years. Such heterozygous females should be alerted to possible hyperammonemic crisis.
Numata
Sanae
S
Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Harada
Eimei
E
Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Maeno
Yasuki
Y
Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Ueki
Isao
I
Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Watanabe
Yoriko
Y
Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Fujii
Chieko
C
Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Yanagawa
Takashi
T
Biostatistics Center, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Takenaka
Satoshi
S
Division of Pediatrics, Oita Prefecture Hospital, 476, Bunyo, Oita, 870-8511, Japan.
Inoue
Toshiro
T
Division of Pediatrics, Oita Prefecture Hospital, 476, Bunyo, Oita, 870-8511, Japan.
Inoue
Shinkai
S
Department of Pediatrics, Nakatsu Municipal Hospital, 173 Shimoikenaga, Nakatsu, 871-0011, Japan.
Goushi
Terufumi
T
Department of Pediatrics, Nakatsu Municipal Hospital, 173 Shimoikenaga, Nakatsu, 871-0011, Japan.
Yasutake
Tsutomu
T
Department of Internal Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
Mizuta
Toshihiko
T
Department of Internal Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
Yoshino
Makoto
M
Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan. yoshino@med.kurume-u.ac.jp.
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D009954:Ornithine Carbamoyltransferase / Q000235:genetics*; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype
D009954:Ornithine Carbamoyltransferase