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

Abstract

In ten families with late-onset ornithine transcarbamylase (OTC) deficiency in male patients, three mutant alleles-R40H, R277W, and Y55D-were identified. In a total of 20 informative parent-offspring pairs, father-to-daughter transmission and mother-to-offspring transmission occurred in five (25%) and 15 (75%), respectively, indicating that paternal transmission contributes substantially to the pool of these mutant alleles. Relative reproductive fitness of males and females carrying the mutant alleles was calculated to be 0.49 and 0.89, respectively. Comparison of the life span of the mutant alleles, estimated on the basis of these fitness values with those associated with classic phenotype (neonatal onset) in which reproductive fitness of male patients was nil, revealed that mutant alleles associated with the late-onset phenotype were eliminated more slowly. This would allow the late-onset phenotype mutant alleles to be retained more frequently in a population than those associated with classic phenotype. Although heterozygous females carrying the late-onset phenotype mutant alleles were generally asymptomatic, one female carrying the R40H allele died after a hyperammonemic episode at the age of 18 years. Such heterozygous females should be alerted to possible hyperammonemic crisis.

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.…”

“…This mutation has been found among the Japanese population alone to date. 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.…”

“…7,[12][13][14][15]25 The p.Y55D mutation has been found only in two unrelated Japanese families. 10,16 It was not known whether or not the recurring mutations shared a common ancestral origin or had arisen independently. The present study suggests that the p.R40H mutation occurred at least four times, or even five times, if the family 14 is non-Japanese American, in the Japanese and in the Caucasian populations.…”

“…In our previous series of Japanese families, the c.119G4A (p.R40H) mutation was encountered in a cluster. 7,10,15 In addition, we identified another novel mutation, c.163T4G (p.Y55D) in two discrete families. 10,16 It is not known whether or not these mutations share a common ancestral origin or have arisen recurrently.…”

“…9 Such male patients reproduce at a fitness value of 0.49. 10 Although the majority of mutations at human OTC locus are 'private' , being observed in single families only, 11 several mutations have been observed repeatedly in discrete families, [12][13][14] mainly affecting CpG dinucleotides. Among those, the c.119G4A (p.R40H) and c.829C4T (p.R277W) mutations have been repeatedly reported in multiple ethnicities.…”