Ornithine Transcarbamylase Deficiency: Genetics


Ornithine transcarbamylase deficiency, the most common urea cycle disorder, is an X‐linked trait displaying large heterogeneity, including cases of symptomatic heterozygotes and very mild hemizygous individuals. A wide mutational spectrum, comprising more than 500 disease‐associated mutations, is currently known. More than two‐thirds of the mutations are nucleotide replacements at the coding region of the gene. mutations are common being responsible for as much as three‐fourths of female abnormal chromosomes. Recurrent mutations found in different human populations are associated with hypermutable CpG dinucleotides, and these features render diagnosis and genetic counselling, particularly challenging. The responsible gene is, however, an excellent model for research on human mutation, owing to (1) the mode of transmission (allowing direct haplotype ascertainment and evaluation of the role of recombination) and (2) the abundance and diversity of mutations. Treatment strategies involve reduction of protein level intake and stimulation of alternative metabolic pathways or liver transplantation.

Key Concepts

  • OTC is a urea cycle enzyme mainly expressed in the liver.
  • OTC deficiency is an X‐linked disease that presents a heterogeneous phenotypic severity.
  • The mode of inheritance renders the phenotypic severity to be more evident in males.
  • The genotype–phenotype relationship is not straightforward.
  • Epistatic interactions have been detected in the OTC protein.

Keywords: urea cycle; ornithine transcarbamylase deficiency (OTCD); genetics; mutational spectrum; epistasis; treatment

Figure 1. Distribution of OTC mutations at the HGMD (HGMD; http://www.hgmd.org). The total number of mutations currently documented at HGMD is 504 distributed as follows: missense and nonsense (65.3%), splicing (10.5%), gross deletions (9.5%), small deletions (9.1%), small insertions (2.8%), complex rearrangements (1.2%), small indels (0.79%), gross insertions (0.4%) and mutations at regulatory sites (0.4%).
Figure 2. Allele frequencies distributions for the first described polymorphic markers reported in OTC gene (Lys46Arg, IVS3‐8nt A>T, IVS4‐7nt A>G and Gln270Arg): a significant interpopulation heterogeneity is observed (data from Azevedo et al., ).


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Snodgrass PJ (2003) Ornithine Transcarbamylase: Basic Science and Clinical Considerations. Boston/Dordrecht/London: Kluwer Academic Publishers.

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Azevedo, Luisa, Oliveira, Ana Sofia, and Amorim, Antonio(Aug 2017) Ornithine Transcarbamylase Deficiency: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005942.pub2]