A 3‐base pair in‐frame deletion in exon 8 (delGlu272/273) of the ornithine transcarbamylase gene in late‐onset hyperammonemic coma

Segues, Bertrand; Saugier-Veber, Pascale; Rabier, Daniel; Calvas, Patrick; Saudubray, Jean‐Marie; Gilbert‐Dussardier, Brigitte; Bonnefont, Jean‐Paul; Münnich, Arnold

doi:10.1002/(sici)1098-1004(1996)8:4<373::aid-humu13>3.0.co;2-#

Cited by 10 publications

(3 citation statements)

References 5 publications

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“…The enzymatic assay in both liver biopsies showed a decreased OTC activity due to a pH variant form of the enzyme that correlate with the mild clinical phenotype of patients. So far, other genetic lesions mapped in the same OTC gene region (codons 264, 267, 268, 272, 273 and 277) have been correlated with a late onset of the OTC deficiency (Matsuura et al, 1993;Shimadzu et al, 1998;Segues et al, 1996;Finkelstein et al, 1990;Hata et al, 1991;Tuchman et al, 1994).…”

Section: Resultsmentioning

confidence: 99%

Lymphocyte mRNA analysis of the ornithine transcarbamylase gene in Italian OTCD male patients and manifesting carriers: Identification of novel mutations

et al. 2000

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Section: Resultsmentioning

confidence: 99%

Lymphocyte mRNA analysis of the ornithine transcarbamylase gene in Italian OTCD male patients and manifesting carriers: Identification of novel mutations

et al. 2000

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“…Principally, the severity of the mutation is determined in part by the location of the mutated amino acid residue in the tertiary structure of the enzyme and by the type of substitution [2].…”

Section: Discussionmentioning

confidence: 99%

“…Until now, it has been difficult to correlate genotypes with the severity of the phenotype. Nevertheless, it is worth noting that mutations in exons 1 and 5–6 of the OTC gene are mainly found in patients with neonatal‐onset OTC deficiency, while mutations in exons 2–4 and 9 are distributed more evenly between both neonatal and late‐onset OTC deficiency [2]. We report on OTC gene mutations in two families that occurred in the same codon, but showed substitutions of different bases and amino acids.…”

mentioning

confidence: 82%

Late‐onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon

Ploechl¹,

Ploechl²,

Stoeckler-Ipsiroglu

et al. 2001

Clinical Genetics

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We report on late-onset ornithine transcarbamylase (OTC) deficiency in two families with mutations in the same codon, but different base substitutions. Onset of symptoms showed great variation, and five hemizygotes finally died. Clinical diagnosis was late and difficult. In family A, 1 patient also developed the signs of Gilbert's disease. In family B, the index case came to attention as OTC deficiency, after the transplantation of his liver when the recipient died of cerebral edema and hyperammonemia. In family A, the hemizygote males died at the ages of 12 and 18 years; in family B, they died at the ages of 20, 26, and 30 years, respectively. Diagnosis was confirmed by reduced OTC activity in liver specimens. The residual activity in autopsy liver of the index patient in family A was less than the activity in the biopsy of the transplanted liver of the index patient in family B. The molecular investigations showed mutations in exon 2 at codon 40 in the OTC gene in both families. However, different bases were substituted. In family A, the single-base mutation was a cytosine-to-thymine transition (Arg 40 Cys); in family B, it was a guanine-to-adenine transition (Arg 40 His). Published data on in vitro expression studies of the recurrent OTC mutation Arg 40 His have shown little effect on the protein structure of the enzyme. These studies would fit well with our observation of higher OTC activity and later age of onset of symptoms in family B.

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Mutations and polymorphisms in the human ornithine transcarbamylase gene

et al. 2002

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Ornithine transcarbamylase (OTC) deficiency, an X-linked, semidominant disorder, is the most common inherited defect in ureagenesis resulting in hyperammonemia. The previous two mutation updates for the OTC gene were published in 1993 and 1995 and included 36 and 30 mutations respectively. This comprehensive update contains a compilation of 244 mutations including 13 polymorphisms. Twenty-four of the mutations are reported here for the first time. Forty-two percent of the disease-causing mutations are associated with acute neonatal hyperammonemia; 21% were found in patients with late onset disease and approximately 37% were found in manifesting heterozygous females, most of which are presumed to confer a neonatal phenotype in hemizygous males. Also included are residual enzyme activities and residual incorporation of ammonium nitrogen into urea and results of expression studies for a small proportion of the mutations. Most mutations in the OTC gene are "private" and are distributed throughout the gene with paucity of mutation in the sequence encoding the leader peptide (exon 1 and beginning of exon 2) and in exon 7. Almost all mutations in consensus splicing sites confer a neonatal phenotype. Thirteen polymorphisms have been found, several of which are useful for allele tracking in patients in whom the mutation can't be found. Even with sequencing of the entire reading frame and exon/intron boundaries, only about 80% of the mutations are detected in patients with proven OTC deficiency. The remaining probably occur within the introns or in regulatory domains.

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A 3‐base pair in‐frame deletion in exon 8 (delGlu272/273) of the ornithine transcarbamylase gene in late‐onset hyperammonemic coma

Cited by 10 publications

References 5 publications

Lymphocyte mRNA analysis of the ornithine transcarbamylase gene in Italian OTCD male patients and manifesting carriers: Identification of novel mutations

Lymphocyte mRNA analysis of the ornithine transcarbamylase gene in Italian OTCD male patients and manifesting carriers: Identification of novel mutations

Late‐onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon

Mutations and polymorphisms in the human ornithine transcarbamylase gene

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