GM24054

GM24054 LCL from B-Lymphocyte

Description:

ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO; OTC
ORNITHINE CARBAMOYLTRANSFERASE; OTC
DISORDERS OF THE UREA CYCLE

Affected:

Yes

Sex:

Male

Age:

6 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Disorders of the Urea Cycle

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

White

Ethnicity

Not Hispanic/Latino

Country of Origin

USA

Family History

Relation to Proband

proband

Confirmation

Molecular characterization before cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; symptom onset at age 7 months; past hyperammonemic events; OTC pathogenic mutation: 129G>A Arg129HIS; treatments include citrulline arginine supplement, protein restriction, and sodium phenylbutrate; liver transplantation.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by LINE assay

Gene

OTC

Chromosomal Location

Xp21.1

Allelic Variant 1

300461.0025; OTC DEFICIENCY

Identified Mutation

ARG129HIS; Garcia-Perez et al. (1995) used PCR amplification of the 10 OTC exons, single-strand conformation polymorphism (SSCP) analysis, and direct sequencing of PCR-amplified exon 4 to demonstrate an arg129-to-his mutation in the OTC gene. The mutation results in the loss of a unique MspI restriction site that can be used for rapid diagnosis. The same mutation is found in the small spf-ash mouse, a rodent model of mild OTC deficiency, causing a neutral R129H mutation and inefficient splicing at the 5-prime donor site at the exon 4/intron 4 junction, with resultant 4 to 7% residual OTC activity. The mutation was also found in the mother in one case and arose de novo in the second case. In the human cases, residual OTC activity, determined in a male and a female patient, was 1.3 and 3.5% of normal, respectively. Despite this low activity, the surviving patients had developed normally. One of them had reached reproductive age, raising the possibility of paternal transmission of the defect. Tuchman et al. (1996) estimated that approximately 90 different mutations associated with OTC deficiency had been defined. They were able to identify apparently deleterious mutations in 78 consecutive families with OTC deficiency by screening all exons and exon/intron borders using SSCP (in 75 families) or sequencing of the entire coding sequence (in 3 families). Large deletions of 1 or more exons were found in 8% of the families and approximately 10% had small deletions or insertions of 1 to 5 bases. Splice site mutations were found in 18% of families. Contrary to previous reports, recurrent point mutations seemed to be equally distributed among most CpG dinucleotides rather than showing prevalent mutations. No single point mutation had a relative frequency of more than 6.4%. Of the 64 families with nucleotide substitutions, 24 (38%) were G to A with the next most common being C to T (16%) and A to T (11%).