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Analysis of genetic mutations in Chinese patients with systemic primary carnitine deficiency
Lianshu Han1, Fei Wang2, Yu Wang1
1Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
Abstract:
Systemic primary carnitine deficiency (CDSP) is caused by mutations in SLC22A5 gene, which encodes organic cation transporter 2(OCTN2). CDSP leads to skeletal or cardiac myopathy and hepatic encephalopathy. The present study aimed to identify SLC22A5 gene mutations and analyze the potential relationship between genotype and clinical symptoms in 20 Chinese patients with CDSP. The complete coding region of the SLC22A5 gene including intron-exon boundaries were amplified and sequenced in all patients. Eighteen different mutations were found; of which, nine were novel. The mutations clustering in exons 1 and 4 accounted for 66.7% of all mutant alleles (26/39). The c.760C>T (p. R254X) was the most frequent mutation (25.6%, 10/39), suggesting it as an ethnic founder mutation. The relationship between genotype and phenotype was investigated in patients carrying the R254X mutation. Homozygous patients with R254X were late-onset cases who presented with dilated cardiomyopathy and muscle weakness after 1 year of age. Compound heterozygous patients carrying R254X, combined with other missense mutations occurred in very specific positions, dramatically altered OCTN2 protein function. Based on the analysis of case studies, a clear relationship between free carnitine (C0) level in plasma and OCTN2 genotype was not found in the present work, however, the low plasma C0 level could not indicate disease severity or genotype. Further functional studies with a large sample size are required to understand the relationship between R254X mutation and CDSP.
Insights
Systemic primary carnitine deficiency (CDSP) in Chinese patients is linked to SLC22A5 gene mutations. The common R254X mutation is associated with late-onset disease, but carnitine levels don't predict severity.
Area of Science:
- Genetics
- Metabolic Disorders
- Molecular Biology
Background:
- Systemic primary carnitine deficiency (CDSP) results from mutations in the SLC22A5 gene, affecting the organic cation transporter 2 (OCTN2).
- CDSP can manifest as skeletal/cardiac myopathy and hepatic encephalopathy.
- Understanding genotype-phenotype correlations is crucial for managing CDSP.
Purpose of the Study:
- To identify SLC22A5 gene mutations in Chinese CDSP patients.
- To analyze the relationship between specific genotypes and clinical manifestations.
- To investigate the prevalence and significance of the R254X mutation.
Main Methods:
- DNA sequencing of the complete coding region and intron-exon boundaries of the SLC22A5 gene in 20 patients.
- Mutation analysis to identify novel and known variants.
- Genotype-phenotype correlation analysis, focusing on patients with the R254X mutation.
Main Results:
- Eighteen distinct SLC22A5 mutations were identified, with nine being novel.
- Mutations in exons 1 and 4 were common (66.7%).
- The c.760C>T (p. R254X) mutation was the most frequent (25.6%), potentially an ethnic founder mutation. Homozygous R254X patients presented with late-onset dilated cardiomyopathy and muscle weakness. Compound heterozygotes with R254X and specific missense mutations showed altered OCTN2 function. No clear correlation was found between plasma free carnitine levels and OCTN2 genotype or disease severity.
Conclusions:
- The SLC22A5 gene harbors diverse mutations in Chinese CDSP patients, with R254X being a significant founder mutation.
- Genotype influences disease presentation, particularly in R254X carriers.
- Plasma carnitine levels are not reliable indicators of CDSP severity or genotype.
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