title: Genotype-phenotype correlation in primary carnitine deficiency.
abstract: Primary carnitine deficiency is caused by defective OCTN2 carnitine transporters encoded by the SLC22A5 gene. Lack of carnitine impairs fatty acid oxidation resulting in hypoketotic hypoglycemia, hepatic encephalopathy, skeletal and cardiac myopathy. Recently, asymptomatic mothers with primary carnitine deficiency were identified by low carnitine levels in their infant by newborn screening. Here, we evaluate mutations in the SLC22A5 gene and carnitine transport in fibroblasts from symptomatic patients and asymptomatic women. Carnitine transport was significantly reduced in fibroblasts obtained from all patients with primary carnitine deficiency, but was significantly higher in the asymptomatic women's than in the symptomatic patients' fibroblasts (P < 0.01). By contrast, ergothioneine transport (a selective substrate of the OCTN1 transporter, tested here as a control) was similar in cells from controls and patients with carnitine deficiency. DNA sequencing indicated an increased frequency of nonsense mutations in symptomatic patients (P < 0.001). Expression of the missense mutations in Chinese hamster ovary (CHO) cells indicated that many mutations retained residual carnitine transport activity, with no difference in the average activity of missense mutations identified in symptomatic versus asymptomatic patients. These results indicate that cells from asymptomatic women have on average higher levels of residual carnitine transport activity as compared to that of symptomatic patients due to the presence of at least one missense mutation.
authors.affiliation: Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Rose
authors.forename: Cristina Amat
authors.initials: CA
authors.lastname: di San Filippo
authors.forename: Uzochi C
authors.initials: UC
authors.lastname: Ndukwe Erlingsson
authors.forename: Orly
authors.initials: O
authors.lastname: Ardon
authors.forename: Marzia
authors.initials: M
authors.lastname: Pasquali
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
mesh_terms: D000328:Adult; D000818:Animals; D058070:Asymptomatic Diseases; D001692:Biological Transport; D016466:CHO Cells; D009202:Cardiomyopathies / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002331:Carnitine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D004880:Ergothioneine / Q000378:metabolism; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D022124:Hyperammonemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007223:Infant; D009135:Muscular Diseases / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters
chemical_list: D018389:Codon, Nonsense; D027701:Organic Cation Transport Proteins; C109807:SLC22A4 protein, human; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters; D004880:Ergothioneine; D002331:Carnitine