Novel intragenic deletions and point mutations of the ornithine transcarbamylase gene in congenital hyperammonemia

Calvas, Patrick; Segues, Bertrand; Rozet, Jean–Michel; Rabier, Daniel; Bonnefond, Jean-Paul; Münnich, Arnold

doi:10.1002/humu.1380110128

Cited by 10 publications

(3 citation statements)

References 22 publications

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“…Therefore, mutations at this position are highly likely to affect the function of OTCase. Furthermore, the two reported cases of OTCD with mutations at residue C303 presented with neonatal onsets, and only one of these occurred in a female [ 3 , 23 , 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Mutation Study of Malaysian Patients with Ornithine Transcarbamylase Deficiency: Clinical, Molecular, and Bioinformatics Analyses of Two Novel Missense Mutations of the OTC Gene

Ali

Zakaria

Radzi

et al. 2018

BioMed Research International

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Ornithine transcarbamylase deficiency (OTCD), an X-linked disorder that results from mutations in the OTC gene, causes hyperammonemia and leads to various clinical manifestations. Mutations occurring close to the catalytic site of OTCase can cause severe OTCD phenotypes compared with those caused by mutations occurring on the surface of this protein. In this study, we report two novel OTC missense mutations, Q171H and N199H, found in Malaysian patients. Q171H and N199H caused neonatal onset OTCD in a male and late OTCD in a female, respectively. In silico predictions and molecular docking were performed to examine the effect of these novel mutations, and the results were compared with other 30 known OTC mutations. In silico servers predicted that Q171H and N199H, as well as 30 known missense mutations, led to the development of OTCD. Docking analysis indicated that N-(phosphonoacetyl)-L-ornithine (PALO) was bound to the catalytic site of OTCase mutant structure with minimal conformational changes. However, the mutations disrupted interatomic interactions in the catalytic site. Therefore, depending on the severity of disruption occurring at the catalytic site, the mutation may affect the efficiency of mechanism and functions of OTCase.

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Section: Discussionmentioning

confidence: 99%

Mutation Study of Malaysian Patients with Ornithine Transcarbamylase Deficiency: Clinical, Molecular, and Bioinformatics Analyses of Two Novel Missense Mutations of the OTC Gene

Ali

Zakaria

Radzi

et al. 2018

BioMed Research International

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“…The replacement of the basic amino acid arginine by the rather hydrophobic cysteine may explain the possibly more severe phenotype in family A, as Oppliger Leibundgut et al [10] argued that the mutation His 302 Tyr behaves in a similar way. Arg 40 Cys might also act by creating disulphide bonds with the cysteine residue at codon 27 of the leader peptide, thus hampering the membrane translocation of the pre‐protein [11].…”

Section: Discussionmentioning

confidence: 99%

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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“…Four of the POOL-predicted distal residues, Asp140, Tyr160, His272, and Glu299, are spatially aligned with huOTC Asp175, Trp193, His302, and Glu310, respectively. Mutations of these residues are known to occur in patients with OTCD [15,[85][86][87][88][89][90][91].…”

Section: Pool Prediction Of Functionally Important Residuesmentioning

confidence: 99%

Probing remote residues important for catalysis in Escherichia coli ornithine transcarbamoylase

et al. 2020

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Understanding how enzymes achieve their tremendous catalytic power is a major question in biochemistry. Greater understanding is also needed for enzyme engineering applications. In many cases, enzyme efficiency and specificity depend on residues not in direct contact with the substrate, termed remote residues. This work focuses on Escherichia coli ornithine transcarbamoylase (OTC), which plays a central role in amino acid metabolism. OTC has been reported to undergo an induced-fit conformational change upon binding its first substrate, carbamoyl phosphate (CP), and several residues important for activity have been identified. Using computational methods based on the computed chemical properties from theoretical titration curves, sequence-based scores derived from evolutionary history, and protein surface topology, residues important for catalytic activity were predicted. The roles of these residues in OTC activity were tested by constructing mutations at predicted positions, followed by steady-state kinetics assays and substrate binding studies with the variants. First-layer mutations R57A and D231A, second-layer mutation H272L, and thirdlayer mutation E299Q, result in 57-to 450-fold reductions in k cat /K M with respect to CP and 44-to 580-fold reductions with respect to ornithine. Second-layer mutations D140N and Y160S also reduce activity with respect to ornithine. Most variants had decreased stability relative to wild-type OTC, with variants H272L, H272N, and E299Q having the greatest decreases. Variants H272L, E299Q, and R57A also show compromised CP binding. In addition to direct effects on catalytic activity, effects on overall protein stability and substrate binding were observed that reveal the intricacies of how these residues contribute to catalysis.

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Novel intragenic deletions and point mutations of the ornithine transcarbamylase gene in congenital hyperammonemia

Cited by 10 publications

References 22 publications

Mutation Study of Malaysian Patients with Ornithine Transcarbamylase Deficiency: Clinical, Molecular, and Bioinformatics Analyses of Two Novel Missense Mutations of the OTC Gene

Mutation Study of Malaysian Patients with Ornithine Transcarbamylase Deficiency: Clinical, Molecular, and Bioinformatics Analyses of Two Novel Missense Mutations of the OTC Gene

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

Probing remote residues important for catalysis in Escherichia coli ornithine transcarbamoylase

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