Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency

Abstract

Carbamoylphosphate synthetase I deficiency (CPS1D) is a urea-cycle disorder characterized by episodes of life-threatening hyperammonemia. Correct diagnosis is crucial for patient management, but is difficult to make from clinical presentation and conventional laboratory tests alone. Enzymatic or genetic diagnoses have also been hampered by difficult access to the appropriate organ and the large size of the gene (38 exons). In this study, in order to address this diagnostic dilemma, we performed the largest 349-354 DOI 10.1007/s10038-007-0122-9 mutational and clinical analyses of this disorder to date in Japan. Mutations in CPS1 were identified in 16 of 18 patients with a clinical diagnosis of CPS1D. In total, 25 different mutations were identified, of which 19 were novel. Interestingly, in contrast to previous reports suggesting an extremely diverse mutational spectrum, 31.8% of the mutations identified in Japanese were common to more than one family. We also identified two common polymorphisms that might be useful for simple linkage analysis in prenatal diagnosis. The accumulated clinical data will also help to reveal the clinical presentation of this rare disorder in Japan.

Novel Pathogenic Variant (c.580C>T) in the CPS1 Gene in a Newborn With Carbamoyl Phosphate Synthetase 1 Deficiency Identified by Whole Exome Sequencing

“…WES of the proband revealed two heterozygous variants of the CPS1 gene: one novel nonsense pathogenic variant of c.580C>T (p.Gln194*) and one previously known pathogenic frameshift pathogenic variant of c.1547delG (p.Gly516Alafs*5), which has been recurrently reported in Japanese patients with CPS1D [178]. These pathogenic variants were confirmed with Sanger sequencing (Fig.…”

Molecular characterization of CPS1 deletions by array CGH

“…Sequence analysis of the CPS1 cDNA derived from cultured fibroblasts revealed an apparently homozygous mutation c.1760G>A (p.R587H) in exon 16 [14]. This mutation has been previously reported in patients with CPSI deficiency [5,12]. Sequence analysis of the parents revealed that the mother was a carrier of the c.1760G>A (p.R587H) mutation, but the father was not.…”

“…Glycine at amino acid position 982 is evolutionarily conserved from yeast to human, and is predicted to be deleterious by computer algorithms, SIFT [10] and PolyPhen [11]. Two other variants at the same amino acid position, c.2945G>A (p.G982D) and c.2944G>A (p.G982S), have been previously reported in patients with CPSI deficiency [12,13]. Collectively, these data suggested that the c.2945G>T (p.G982V) variant was likely pathogenic.…”

Loss of Hep Par 1 immunoreactivity in the livers of patients with carbamoyl phosphate synthetase 1 deficiency

“…Genomic DNA was isolated from the peripheral blood of patients before the operation. PCR amplification was performed on the DNA as previously reported …”

“…In newborn patients, hyperammonemia manifests after feeding commencement, with symptoms such as vomiting, hypothermia, somnolence, lethargy, apnea, seizure, or coma. Though the initial medical treatment of CPS1D consists of protein restriction and medications such as sodium phenylbutyrate, only liver transplantation can offer complete avoidance of recurrent hyperammonemia and prevent serious neurological damage . Various types of mutations causing CPS1D have been reported, but missense mutations are the most frequently observed .…”