Phenotypic variability in male patients carrying the mutant ornithine transcarbamylase (OTC) allele, Arg40His, ranging from a child with an unfavourable prognosis to an asymptomatic older adult.

Matsuda, Ichiro; Matsuura, Toshinobu; Nishiyori, Atsushi; Komaki, Satoru; Hoshide, Ryuuji; Matsumoto, Tadashi; Funakoshi, Mitsuhiko; Kiwaki, Kohji; Endo, Fumio; Hata, Akira; Shimadzu, Mitsunobu; Yoshino, Makoto

doi:10.1136/jmg.33.8.645

Cited by 32 publications

(38 citation statements)

References 18 publications

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“…844 transfected cells is equivalent to that seen in cells expressing the wild-type enzyme. On the other hand, the R40H mutant protein showed residual OTC activity of approximately 26 to 35% of wild type, consistent with a much milder phenotype and occasionally lack of symptoms (6). In addition, the amount of R40H mutant protein is markedly reduced to about the same degree in both stable and transient expression systems.…”

Section: Discussionmentioning

confidence: 67%

Expression of Wild-Type and Mutant Human Ornithine Transcarbamylase Genes in Chinese Hamster Ovary Cells and Lack of Dominant Negative Effect of R141Q and R40H Mutants

et al. 2000

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Chinese hamster ovary cultured cells were transformed to continuously express wild-type and two mutant ornithine transcarbamylase genes, R141Q and R40H. In addition, these cells were transfected to transiently express the same genes. The R141Q mutation abolishes the enzymatic activity, and the amount of "mature" protein present in transfected cells is equivalent to the wild type. The R40H mutation causes a reduction of enzymatic activity to approximately 26 to 35% of wild type concomitant with a significant reduction in the amount of protein present. Transfection with wild-type and mutant genes together in various proportions did not reveal dominant negative effects of the two mutations studied. This expression system can be used to examine the deleterious effect of private mutations or lack thereof in families with ornithine transcarbamylase deficiency as well as evaluate the potential dominant negative effects of gene delivery for treatment of ornithine transcarbamylase deficiency. The enzyme OTC (EC 2.1.3.3) catalyzes the conversion of ornithine and carbamyl phosphate to citrulline and inorganic phosphate. Human OTC is expressed from a gene on the X chromosome as an inactive precursor polypeptide containing a 32 amino acid N-terminal signal sequence that is cleaved upon transport into the mitochondria, where the active homotrimeric enzyme is formed (1). Mutations in the OTC gene result in varying degrees of OTCD, causing hyperammonemia due to decreased synthesis of urea in the liver.More than 130 apparently deleterious "private" mutations of the human OTC gene have been observed in families affected by OTCD (2). Although some of the mutations are deletions or insertions that are readily identified as causing OTCD, over 80% are single-base substitutions, and only a few of these have been examined in expression studies to confirm and investigate altered biochemical and/or molecular mechanisms.Following the initial isolation of human OTC cDNA and study of its expression in HeLa cells (3), it was demonstrated that a C to T transition in codon 141 (R141Q) observed in OTCD newborns with acute neonatal hyperammonemic coma resulted in a complete loss of enzyme activity when the mutant cDNA was expressed in Cos1 cells (4). Because arginine 141 is one of the active site residues that binds to one of the oxygen atoms of carbamyl phosphate (5), its replacement will directly affect substrate binding. On the other hand, the R40H mutation is associated with an extremely variable phenotype and the mechanism of its deleterious effect is unknown. When expressed in Cos1 cells, only 10% of control activity was observed (6). Subsequently, it was shown that mRNA transcribed from R40H cDNA was equal in both abundance and stability to that transcribed from wild-type cDNA, however, it was found that the R40H protein was less abundant than wild-type OTC (7). In our laboratory, an in vitro study of mature human OTC protein showed that the biochemical and physical properties of the R40H protein were indistinguishable from wild-type OTC ...

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Section: Discussionmentioning

confidence: 67%

Expression of Wild-Type and Mutant Human Ornithine Transcarbamylase Genes in Chinese Hamster Ovary Cells and Lack of Dominant Negative Effect of R141Q and R40H Mutants

et al. 2000

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“…Although the Australian family has no known Spanish ancestry, the proband's maternal grandfather (not studied) was of North Italian descent and could conceivably share ancestry with the Spanish family. It remains possible that the mutation occurred recurrently, but it is noteworthy that the allele in these families has a low haplotype frequency (0.033) among 25 Present report Present report Arranz et al 27 Pinner et al 28 Plöchl et al 23 Tuchman et al, 11 Tuchman et al 10 Kim et al 29 McCullough et al 14 Nishiyori et al 16 Caucasians. Families 12 and 13 share a haplotype, but there is insufficient information to say whether this represents the effect of common ancestry or of recurrence on the same haplotype.…”

Section: Discussionmentioning

confidence: 77%

“…12 Among mutations associated with late-onset OTCD in male patients, the two mutations, p.R40H and p.R277W, have been most frequently reported in multiple different families. 7,[12][13][14][15]25 The p.Y55D mutation has been found only in two unrelated Japanese families. 10,16 It was not known whether or not the recurring mutations shared a common ancestral origin or had arisen independently.…”

Section: Discussionmentioning

confidence: 99%

Mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients have recurrently arisen and have been retained in some populations

et al. 2009

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We performed haplotype analysis using nine single nucleotide polymorphisms in the ornithine transcarbamylase gene to explore the ancestral origins of three mutations associated with late-onset phenotype in male patients: p.R40H, p.R277W and p.Y55D. Overall, 8 haplotypes were defined among 14 families carrying p.R40H, 5 families carrying p.R277W and 2 families with p.Y55D mutations. Of nine Japanese families carrying p.R40H, eight exhibited haplotype (HT)1, whereas the other family harbored HT2. Among three Caucasian families, one Spanish and one Australian family bore HT3; one Austrian family had HT4. Two US patients harbored HT2 and HT4. Among families carrying p.R277W, HT5 was found in one Japanese, one Korean and one US family. Two other US families had HT2 and HT6. Two families carrying p.Y55D, both Japanese, shared HT1. These results indicate that the p.R40H mutation has arisen recurrently in all populations studied, although there is evidence for a founder effect in Japan, with most cases probably sharing a common origin, and to a lesser extent in subjects of European ancestry (HT3). It is evident that p.R277W mutation has recurred in discrete populations. The p.Y55D mutation appears to have arisen from a common ancestor, because this transversion (c.163T4G) occurs rarely.

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“…If the inherited susceptibility allele is present but other factors are absent, the disease will not develop, that is, the allele is incompletely penetrant. Even in Mendelian diseases, the same inherited mutation may not always lead to symptoms, or the age at onset and the severity of symptoms may vary considerably (47).…”

Section: Penetrancementioning

confidence: 99%

Ethical and Legal Issues in Genetic Epidemiology

Holtzman

Andrews

1997

Epidemiologic Reviews

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Phenotypic variability in male patients carrying the mutant ornithine transcarbamylase (OTC) allele, Arg40His, ranging from a child with an unfavourable prognosis to an asymptomatic older adult.

Abstract: In five different Japanese families, we identified six male hemizygotes (aged 6, 9, 15, 17, 56, and 65 years)

Cited by 32 publications

References 18 publications

Expression of Wild-Type and Mutant Human Ornithine Transcarbamylase Genes in Chinese Hamster Ovary Cells and Lack of Dominant Negative Effect of R141Q and R40H Mutants

Expression of Wild-Type and Mutant Human Ornithine Transcarbamylase Genes in Chinese Hamster Ovary Cells and Lack of Dominant Negative Effect of R141Q and R40H Mutants

Mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients have recurrently arisen and have been retained in some populations

Ethical and Legal Issues in Genetic Epidemiology

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