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

Abstract

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.

Mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients have recurrently arisen and have been retained in some populations

“…Although the Australian family has no known Spanish ancestry, the proband's maternal grandfather (not studied) was of North Italian descent and could conceivably share ancestry with the Spanish family. It remains possible that the mutation occurred recurrently, but it is noteworthy that the allele in these families has a low haplotype frequency (0.033) among 25 Present report Present report Arranz et al 27 Pinner et al 28 Plöchl et al 23 Tuchman et al, 11 Tuchman et al 10 Kim et al 29 McCullough et al 14 Nishiyori et al 16 Caucasians. Families 12 and 13 share a haplotype, but there is insufficient information to say whether this represents the effect of common ancestry or of recurrence on the same haplotype.…”

“…10,16 In contrast to the p.R40H and p.R277W mutations, which involve CpG dinucleotides and hence are likely to recur, this transversion (T-to-G) is not common among single base substitutions in X chromosome genes in general 26 and in the OTC gene in particular. 12,14,27 This characteristic of the p.Y55D mutation would again support that the affected families share a common ancestral origin.…”

“…Recurrent point mutations occur evenly among most CpG dinucleotides in the OTC gene. 9,12,14,27 These two mutations arise in arginine codons. It is not surprising that these single nucleotide changes have a higher chance to recur than others, because four of six codons that encode for arginine contain CpG dinucleotides.…”

Paternal transmission and slow elimination of mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients

“…In contrast, certain mutations were repeatedly found in families in the series reported here that are reportedly unrelated, although all the R40H mutant alleles in the series were found in families living in an area with a radius of 120 km, suggesting a possible common ancestral origin. In addition, this mutant allele has occurred recurrently (Tuchman et al 1995;Plöchl et al 1999;Arranz et al 2007;Pinner et al personal communication). Thus, R40H alleles may be maintained mostly by transmission from ancestors to their offspring, with occasional addition by de novo mutation.…”

“…However, the R40H mutation has been found in discrete families in the Japanese population (Matsuda et al 1996;Nishiyori et al 1997;Harada et al 2006) and in other ethnic groups (Tuchman et al 1995;Plöchl et al 1999;Arranz et al 2007). The R277W mutation was also found in multiple families with different ethnic origins (Finkelstein et al 1990b;Hata et al 1991;Matsuura et al 1993; present series).…”