Journal
HUMAN MUTATION
Volume 19, Issue 2, Pages 93-107Publisher
WILEY
DOI: 10.1002/humu.10035
Keywords
ornithine carbamoyl transferase; ornithine transcarbamylase; OTC; urea cycle; X-linked; hyperammonemia; metabolic disease; private mutations
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Funding
- NCRR NIH HHS [MO1-RR13297] Funding Source: Medline
- NIDDK NIH HHS [R01-DK47870] Funding Source: Medline
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR013297] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK047870] Funding Source: NIH RePORTER
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Ornithine transcarbamylase (OTC) deficiency, an X-linked, semidominant disorder, is the most common inherited defect in ureagenesis resulting in hyperammonemia. The previous two mutation updates for the OTC gene were published in 1993 and 1995 and included 36 and 30 mutations respectively. This comprehensive update contains a compilation of 244 mutations including 13 polymorphisms. Twenty-four of the mutations are reported here for the first time. Forty-two percent of the disease,causing mutations are associated with acute neonatal hyperammonemia; 21% were found in patients with late onset disease and approximately 37% were found in mania festing heterozygous females, most of which are presumed to confer a neonatal phenotype in hemizygous males. Also included are residual enzyme activities and residual incorporation of ammonium nitrogen into urea and results of expression studies for a small proportion of the mutations. Most mutations in the OTC gene are private and are distributed throughout the gene with paucity of mutation in the sequence encoding the leader peptide (exon 1 and beginning of exon 2) and in exon 7. Almost all mutations in consensus splicing sites confer a neonatal phenotype. Thirteen polymorphisms have been found, several of which are useful for allele tracking in patients in whom the mutation cant be found. Even with sequencing of the entire reading frame and exon/intron boundaries, only about 80% of the mutations are detected in patients with proven OTC deficiency. The remaining probably occur within the introns or in regulatory domains. Hum Mutat 19:93-107, 2002. (C) 2002 Wiley-Liss, Inc.
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