Ornithine Transcarbamylase Deficiency: Genetics

Luísa Azevedo, IPATIMUP (Instituto de Patologia e Imunologia Molecular da Universidade do Porto), Porto, Portugal
António Amorim, IPATIMUP (Instituto de Patologia e Imunologia Molecular da Universidade do Porto), Faculdade de Ciências da Universidade do Porto, Porto, Portugal

Published online: July 2007

DOI: 10.1002/9780470015902.a0005942

Full Article on Wiley Online Library

Ornithine transcarbamylase deficiency, the most common urea cycle disorder, is an X-linked trait displaying large phenotypic heterogeneity, which includes cases of symptomatic heterozygotes and wide mutational spectrum. Moreover, de novo mutations are common, particularly in the male gametogenesis, being responsible for as much as three-fourth of female abnormal chromosomes. Recurrent mutations found in different human populations are associated with hypermutable CpG dinucleotides. These features render diagnosis, genetic counselling and treatment particularly difficult. The responsible gene is, however, an excellent model for research on human mutation, due to (a) the mode of transmission (allowing direct haplotype ascertainment and evaluation of the role of recombination, which occurs only in females) and (b) the abundance and diversity of mutations. Treatment strategies involve reduction of protein level intake and stimulation of alternative metabolic pathways or liver transplantation.

Keywords: ornithine transcarbamylase (OTC); deficiency; genetics; mutation; diagnosis; treatment

References
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Further Reading
	Hata A, Tsuzuki T, Shimada K et al. (1986) Isolation and characterization of the human ornithine transcarbamylase gene: structure of the 5¢-end region. Journal of Biochemistry 100: 717–725.
	Horwich AL, Kalousek F, Fenton WA, Pollock RA and Rosenberg LE (1986) Targeting of pre-ornithine transcarbamylase to mitochondria: definition of critical regions and residues in the leader peptide. Cell 44: 451–459.
	Nagasaka H, Yorifuji T, Egawa H et al. (2001) Successful living-donor liver transplantation from an asymptomatic carrier mother in ornithine transcarbamylase deficiency. The Journal of Pediatries 138: 432–434.
	Oppliger Leibundgut EO, Liechti-Gallati S, Colombo JP and Wermuth B (1995) Ornithine transcarbamylase deficiency: new sites with increased probability of mutation. Human Genetics 95: 191–196.
	Plante RJ and Tuchman M (1998) Polymorphisms in the human ornithine transcarbamylase gene useful for allele tracking. Mutations in brief no. 193. Human Mutation 12: 289–290.
	book Snodgrass PJ (2003) Ornithine transcarbamylase: basic science and clinical considerations. Boston/Dordrecht/London: Kluwer Academic Publishers.
	Tuchman M, Plante RJ, Garcia-Perez MA and Rubio V (1996) Relative frequency of mutations causing ornithine transcarbamylase deficiency in 78 families. Human Genetics 97: 274–276.

Article Title:	Ornithine Transcarbamylase Deficiency: Genetics
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	Figure 1. Mutations at the OTC gene. (a) Relative frequency of single-base substitutions, small insertions and deletions (indels) and large deletions. (b) Type of nucleotide substitutions at CpG sites. (c) Density of mutations (total and independent) and CpG sites per exon, normalized to the exon length. Total number of mutations reported so far is 341 (data from Yamaguchi et al., 2006).
	Figure 2. Allele frequencies distributions for the first described polymorphic markers reported in OTC gene (K46R, IVS3-8nt A>T, IVS4-7nt A>G and Q270R): a significant inter-population heterogeneity is observed (data from Azevedo et al., 2003).

Ornithine Transcarbamylase Deficiency: Genetics

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