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Genotype–phenotype correlation in primary carnitine deficiency

Authors

  • Emily C. Rose,

    1. Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, Utah
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  • Cristina Amat di San Filippo,

    1. Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, Utah
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  • Uzochi C. Ndukwe Erlingsson,

    1. Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, Utah
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  • Orly Ardon,

    1. Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, Utah
    2. ARUP Institute for Clinical and Experimental Pathology®, ARUP Laboratories, Salt Lake City, Utah
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  • Marzia Pasquali,

    1. Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, Utah
    2. ARUP Institute for Clinical and Experimental Pathology®, ARUP Laboratories, Salt Lake City, Utah
    3. Department of Pathology, University of Utah, Salt Lake City, Utah
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  • Nicola Longo

    Corresponding author
    1. Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, Utah
    2. ARUP Institute for Clinical and Experimental Pathology®, ARUP Laboratories, Salt Lake City, Utah
    3. Department of Pathology, University of Utah, Salt Lake City, Utah
    • Division of Medical Genetics, Department of Pediatrics, University of Utah, 2C412 SOM, 50 North Mario Capecchi Drive, Salt Lake City, UT 84132.
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  • Communicated Johannes Zschocke

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. Hum Mutat 33:118–123, 2012. © 2011 Wiley Periodicals, Inc.

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