The ornithine transcarbamylase (OTC) gene: Mutations in 50 Japanese families with OTC deficiency

Abstract

Mutations in the OTC gene in 50 Japanese families with OTC deficiency were reviewed in relation to the phenotype of the patients and predicted structure of the mutant enzyme. Similar to other X-linked diseases, mutant alleles in OTC deficiency are highly heterogeneous. Mutations observed in male patients with neonatal onset of the disease included base insertion/deletion, exon skipping, and nonsense and missense mutations in exon 4, 5, 6, or 7. OTC activity was essentially undetectable in this group of patients. These mutations possibly resulted in unstable mRNA or truncated protein, or involved the active site or core domain of the enzyme leading to structural changes. In male patients with late onset, abnormalities observed were missense mutations in exons 2, 4, 8, 9, and 10, and missense mutations plus donor site errors involving exons 4, 5, and 6. OTC activity in these patients was 8.1 +/- 6.3% of the control and most mutations occurred on the surface of the protein. In female patients, age at onset ranged from 19 months to 7 years, depending on residual OTC activities (4.5 to 33% of the control). Most mutations in this group were similar to those seen in male patients with neonatal onset, i.e., nonsense and missense mutations in exons 5 and 6, and exon skipping, leading to null enzyme activity. These collective data can serve for genetic counseling and monitoring in prenatal care.

Defective Ureagenesis in Mice Carrying a Liver-specific Disruption of Hepatocyte Nuclear Factor 4α (HNF4α)

“…Many mutations were identified in the exons and exon/intron borders (51,52), but no mutations have yet been reported in the regulatory elements. However, mutations in the HNF4␣-binding site were reported in other human genes, such as blood coagulation factor VII (53), IX (54 -56), and HNF1␣ (57).…”

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

“…12 Among mutations associated with late-onset OTCD in male patients, the two mutations, p.R40H and p.R277W, have been most frequently reported in multiple different families. 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.…”

“…Demographic information, including ethnic background, of the US families (13,14,(17)(18)(19) was not available because of the US Personal Data Protection Act. Haplotype analysis was performed on the proband from each family and their relatives, when specimens were available from them.…”

“…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.…”

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

“…The majority of mutations at the OTC locus are ''private'' in male patients with classic presentation (Tuchman et al 1995;Matsuda and Tanase 1997). 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).…”