Journal of Inherited Metabolic Disease

, Volume 30, Issue 2, pp 217–226 | Cite as

Estimation of the total number of disease-causing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential

  • J. A. Arranz
  • E. Riudor
  • C. Marco-Marín
  • V. Rubio
Original Article


Ornithine transcarbamylase deficiency (OTCD), the X-linked, most frequent urea cycle error, results from mutations in the OTC gene, encoding a 354-residue polypeptide. To date 341 OTCD clinical mutations, including 222 missense single nucleotide changes (mSNCs), have been compiled (Hum Mutat 2006;27:626). OTCD mutation detection might be simplified if the entire repertoire of OTCD-causing mutations were known. We estimate the size of this repertoire from 23 new OTCD patients exhibiting 22 different mutations, of which 9, including 4 mSNCs, are novel. The complete repertoire of OTCD-causing mutations is estimated as 560 mutations (95% confidence interval, 422–833 mutations), including 290 mSNCs (95% confidence interval, 230–394 mSNCs). Thus, OTCD diagnosis based on the screening for known mutations might attain ˜90% sensitivity in <5 years. Since disease-causing mSNCs represent <20% of the 2064 possible OTC mSNCs, simple approaches are essential for discrimination between causative and trivial mSNCs. Observation of the OTC structure appears a simple approach for such discrimination, comparing favourably in our sample with three formalized structure-based and/or sequence-based in silico assessment methods, and supporting the causation of complete deficiency by the mutations p.Pro305Arg and p.Ser96Phe, and of partial deficiency by p.Asp41Gly, p.Glu122Gly, p.Leu179Phe, p.Pro220Thr and p.Glu273del. Five non-mSNC novel mutations (p.Gly71X, a 7-nucleotide and a 10-nucleotide duplication and deletion in exon 5, G>A transitions at bases +1 and +5 of introns 4 and 9, respectively) are obviously pathogenic. The previously reported mSNCs p.Arg26Gln, p.Arg40His, p.Glu52Lys, pLys88Asn, p.Arg129His, p.Asn161Ser, p.Thr178Met, p.His202Tyr, p.Ala208Thr and p.His302Arg, found in our cohort, are also discussed.


Ornithine Carbamoyl Phosphate Ornithine Transcarbamylase Acta Crystallogr Sect Clinical Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



confidence interval


missense single nucleotide change


nonsense single nucleotide change


ornithine transcarbamylase


ornithine transcarbamylase deficiency




single nucleotide change


single-strand conformational polymorphism


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Copyright information

© SSIEM and Springer 2007

Authors and Affiliations

  • J. A. Arranz
    • 1
  • E. Riudor
    • 1
  • C. Marco-Marín
    • 2
  • V. Rubio
    • 2
  1. 1.Unitat de MetabolopatiesHospital Materno-Infantil Vall d’HebronBarcelonaSpain
  2. 2.Instituto de Biomedicina de Valencia and CIBER de Enfermedades RarasValenciaSpain

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