A novel missense mutation in exon 8 of the ornithine transcarbamylase gene in two unrelated male patients with mild ornithine transcarbamylase deficiency

Hata, Akira; Matsuura, Toshinobu; Setoyama, Chiaki; Shimada, Kazuniro; Yokoi, Takeshi; Akaboshi, Izumi; Matsuda, Ichiro

doi:10.1007/bf01213087

Cited by 29 publications

(26 citation statements)

References 24 publications

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“…All five hemizygotes had a normal life until age 9-18 years, but contact with them was subsequently lost. OTC activity in the patients was ∼19% of the control and K m for ornithine at pH 7.5 was approximately 10 times higher than that for the control [Hata et al, 1991]. The same point mutation was noted by Finkelstein et al [1990] in a patient with late onset of the disease.…”

Section: R277wmentioning

confidence: 57%

The ornithine transcarbamylase (OTC) gene: Mutations in 50 Japanese families with OTC deficiency

Matsuda

Tanase

1997

Am. J. Med. Genet.

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Mutations in the OTC gene in 50 Japanese families with OTC deficiency were reviewed in relation to the phenotype of the patients and predicted structure of the mutant enzyme. Similar to other X-linked diseases, mutant alleles in OTC deficiency are highly heterogeneous. Mutations observed in male patients with neonatal onset of the disease included base insertion/deletion, exon skipping, and nonsense and missense mutations in exon 4, 5, 6, or 7. OTC activity was essentially undetectable in this group of patients. These mutations possibly resulted in unstable mRNA or truncated protein, or involved the active site or core domain of the enzyme leading to structural changes. In male patients with late onset, abnormalities observed were missense mutations in exons 2, 4, 8, 9, and 10, and missense mutations plus donor site errors involving exons 4, 5, and 6. OTC activity in these patients was 8.1 +/- 6.3% of the control and most mutations occurred on the surface of the protein. In female patients, age at onset ranged from 19 months to 7 years, depending on residual OTC activities (4.5 to 33% of the control). Most mutations in this group were similar to those seen in male patients with neonatal onset, i.e., nonsense and missense mutations in exons 5 and 6, and exon skipping, leading to null enzyme activity. These collective data can serve for genetic counseling and monitoring in prenatal care.

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Section: R277wmentioning

confidence: 57%

The ornithine transcarbamylase (OTC) gene: Mutations in 50 Japanese families with OTC deficiency

Matsuda

Tanase

1997

Am. J. Med. Genet.

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“…Mutations in codon 277 have thus far been associated only with a milder phenotype presenting clinically after the newborn period. The R277W mutation was associated with the presence of residual enzymatic activity (2-16% of normal; Finkelstein et al, 1990;Hata et al, 1991) as documented also by expression studies (Tuchman et al, 199413). The newly described R277Q mutation found by the authors represents a very mild OTC A mutation in exon 4 which is identical to that of the sparse-fur-ASH mouse (R129H) was found in a female with OTC deficiency (Tuchman et al, 1 9 9 4~) .…”

mentioning

confidence: 84%

Mutations and polymorphisms in the human ornithine transcarbamylase gene: Mutation update addendum

Tuchman

Plante

1995

Hum. Mutat.

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This mutation update addendum summarizes 30 new mutations and polymorphisms found in the ornithine transcarbamylase (OTC) gene since the publication in this journal of the first mutation update. Thus, more than 60 mutations and polymorphisms in the OTC gene are currently known. Most of the mutations have been seen in a single family and the few recurrent mutations occurred in CpG dinucleotides. The presumed deleterious effects of most mutations await confirmation by appropriate expression studies. Once the tertiary structure of the enzyme is fully known, and the functional domains established, the effects of mutations, or lack thereof, could be better predicted.

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“…In this instance, a lower than normal amount of preOTC was transported into the mitochondrial matrix, giving rise to mature OTC at a decreased concentration but one which was still sufficient for minimum essential nitrogen disposal. Several missense mutations involving the putative ornithine binding site (Finkelstein et al 1990;Hata et al 1991;Matsuura et al 1993) and the putative carbamylphosphate binding site (Tuchman et al 1992;Tsai et al 1993) are known. These mutant OTCs are very likely to exhibit a lower affinity towards ornithine or carbamylphosphate but to retain some residual activity, depending on the substrate concentration.…”

Section: Introductionmentioning

confidence: 99%

The R40H mutation in a late onset type of human ornithine transcarbamylase deficiency in male patients

et al. 1997

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Ornithine transcarbamylase (OTC) deficiency is an X-linked trait and is one of the most frequent of the inherited urea cycle enzyme deficiencies. Most male patients with OTC deficiency develop a hyperammonemic crisis and die in the neonatal period or in early infancy. In contrast to those patients, in some male patients the disease first becomes overt in adolescence or during the reproductive age period. In the present report, we describe six such male patients who first developed clinical signs at ages ranging from 6 to 58 years, all of whom came from a limited area of the northern part of Kyushu Island in southern Japan. The mutation analysis disclosed a R40H mutation in exon 2 of the OTC gene in each of these patients. Transmission of this mutant gene through paternal lineage as well as through maternal lineage was documented in one family. The levels of mRNA of the mutant OTC gene expressed in transfected Cos 1 cells and in the liver tissue obtained by biopsy in one patient were both similar to those of the wild-type gene. The activity of the mutant OTC was, however, decreased to a level of 28% of the wild-type OTC, and the levels of the mutant OTC protein expressed in Cos 1 cells were decreased, as assessed by western blot analysis. Apparent Km values of the mutant enzyme for ornithine (1.1 mM) and carbamylophosphate (2.0 mM) were similar to those of the wild-type enzyme. Both enzymes gave similar pH-dependency profiles, giving a maximal activity at pH 7.8-7.9. Activity of wild-type OTC expressed in Cos 1 cells did not change after five cycles of freezing and thawing, whereas that of the mutant OTC decreased to 17% by this treatment. These results suggest that deficiency is due to inactivation of the mutant OTC under certain conditions.

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A novel missense mutation in exon 8 of the ornithine transcarbamylase gene in two unrelated male patients with mild ornithine transcarbamylase deficiency

Cited by 29 publications

References 24 publications

The ornithine transcarbamylase (OTC) gene: Mutations in 50 Japanese families with OTC deficiency

The ornithine transcarbamylase (OTC) gene: Mutations in 50 Japanese families with OTC deficiency

Mutations and polymorphisms in the human ornithine transcarbamylase gene: Mutation update addendum

The R40H mutation in a late onset type of human ornithine transcarbamylase deficiency in male patients

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