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Arginine to cysteine mutation (R499C) found in a Japanese patient with complete myeloperoxidase deficiency.

ABSTRACT: Animal models suggest that a deficiency in myeloperoxidase (MPO; EC 1.11.1.7), a lysosomal hemoprotein involved in host defense, may be associated with a decreased level of immunity. A nonsynonymous mutation, resulting in an arginine to cysteine substitution (Arg499Cys or R499C), has been identified in the exon 9 genetic coding region of a Japanese patient with complete MPO deficiency. Genetic analysis revealed that the mRNA of the patient could be correctly transcribed then further translated into a peptide sequence. However, the Western blot analysis confirmed the absence of MPO peptides. An initial screening assay of the patient's blood exhibited an abnormal hematograph, and no MPO activity was detected. To determine if this mutation might be associated with MPO deficiency, DNA samples for 387 controls were examined. Genetic analysis was performed using standard PCR techniques for amplification and sequencing. None of the control samples possessed the R499C substitution. This mutation is in close proximity to a different mutation (G501S) previously found in another Japanese MPO-deficient patient, and the amino acid, H502, which is strongly involved in heme binding, leading to the speculation that heme binding may play a role in complete MPO deficiency.

SUBMITTER: Persad AS

PROVIDER: S-EPMC6032473 | biostudies-literature | 2006

REPOSITORIES: biostudies-literature

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Arginine to cysteine mutation (R499C) found in a Japanese patient with complete myeloperoxidase deficiency.

Persad Amanda S AS Kameoka Yosuke Y Kanda Shuji S Niho Yoshiyuki Y Suzuki Kazuo K

Gene expression 20060101 2

Animal models suggest that a deficiency in myeloperoxidase (MPO; EC 1.11.1.7), a lysosomal hemoprotein involved in host defense, may be associated with a decreased level of immunity. A nonsynonymous mutation, resulting in an arginine to cysteine substitution (Arg499Cys or R499C), has been identified in the exon 9 genetic coding region of a Japanese patient with complete MPO deficiency. Genetic analysis revealed that the mRNA of the patient could be correctly transcribed then further translated i ...[more]

PMID: 17017121

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Project description:Early recognition of rare mitochondrial respiratory chain defects has become readily available with the routine use of whole exome sequencing. Patients with oxidative phosphorylation defects present with a heterogenous phenotype, often rapidly progressive, and lethal. Clinicians aim for prompt identification of the specific molecular defect to provide timely management, decrease morbidity, and potentially improve survival rates. More recently, bi-allelic pathogenic variants in the TRMU gene responsible for encoding the mitochondrial tRNA-specific 2-thiouridylase were found in a syndrome characterized by infantile hepatopathy due to a mitochondrial translation defect (OMIM# 613070). This nuclear encoded enzyme catalyzes the addition of a sulfur-containing thiol group to the wobble position of mitochondrial specific tRNAs. TRMU deficiency is characterized by a combined respiratory chain deficiency without associated mitochondrial DNA depletion. This mitochondrial tRNA-modifying enzyme requires sulfur for its activity. Previous cellular models have suggested supplementation with cysteine, one of the sulfur containing amino acids, may play a role in increasing thiouridylation levels of mt-tRNAs by increasing sulfur availability for TRMU activity. Cysteine is considered a conditional essential amino acid due to limited availability in infants caused by immature cystathionine gamma-lyase (cystathionase) enzyme activity. The potential benefit of L-cysteine supplementation in TRMU deficiency has been previously proposed to ameliorate the severity and insidious course of the disease. Here we report the clinical, biochemical, and genetic findings of two siblings presenting with hepatopathy associated with hyperlactatemia due to bi-allelic pathogenic variants in TRMU. One patient died due to related complications. The other case was diagnosed prenatally allowing early implementation of L-cysteine supplementation, recovery of liver function, and avoidance of liver transplantation.

Dataset Information

Arginine to cysteine mutation (R499C) found in a Japanese patient with complete myeloperoxidase deficiency.

Publications

Arginine to cysteine mutation (R499C) found in a Japanese patient with complete myeloperoxidase deficiency.

Similar Datasets

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