The objective of this project is to characterize the role of carnitine transporters in human disease. Carnitine transfers long-chain fatty acids across the mitochondrial membrane for subsequent beta oxidation. A defect in the high-affinity OCTN2 carnitine transporter causes primary carnitine deficiency characterized by hypoketotic hypoglycemia and/or skeletal/cardiac myopathy. This phenotype has now expanded with the identification of symptoms of carnitine deficiency in patients with only partially impaired carnitine transport and adult patients (age 24-37) with 2 mutations in the carnitine transporter gene completely asymptomatic. We hypothesize that this phenotypic variability can be due to unusual OCTN2 mutations, to the contribution of other carnitine transporters, or to the effect of other genes encoding proteins interacting with OCTN2 or involved in fatty acid oxidation. To test this hypothesis, we will define the effect on function of unusual OCTN2 mutations, evaluate activity and sequence of other carnitine transporters, define proteins interacting with the OCTN2 carnitine transporter and look for alterations in their genes in patients with unusual forms of carnitine deficiency. The following specific aims will be accomplished:
Aim 1. Study mutations in the OCTN2 carnitine transporter of patients with unusual phenotype of carnitine deficiency. We will exclude a possible dominant-negative effect of the mutation identified, synergistic heterozygosity with mutations in other fatty acid oxidation genes and variations in other carnitine transporters.
Aim 2. Identification of proteins interacting with the carnitine transporter OCTN2 using the 2-hybrid system. Mutations in the genes identified will be sought in symptomatic patients with partial carnitine deficiency and no mutations in the carnitine transporter gene. This study will expand the phenotype of carnitine deficiency, clarify the molecular basis of unusual forms of carnitine deficiency, define the importance of intracellular protein networks in the functioning of membrane transporters, and identify the possible role of minor carnitine transporters in human disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
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Sechi, Salvatore
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Frigeni, Marta; Balakrishnan, Bijina; Yin, Xue et al. (2017) Functional and molecular studies in primary carnitine deficiency. Hum Mutat 38:1684-1699
Frigeni, Marta; Iacobazzi, Francesco; Yin, Xue et al. (2016) Wide tolerance to amino acids substitutions in the OCTN1 ergothioneine transporter. Biochim Biophys Acta 1860:1334-42
Longo, Nicola; Frigeni, Marta; Pasquali, Marzia (2016) Carnitine transport and fatty acid oxidation. Biochim Biophys Acta 1863:2422-35
Ndukwe Erlingsson, Uzochi Chimdinma; Iacobazzi, Francesco; Liu, Aiping et al. (2013) The effect of valinomycin in fibroblasts from patients with fatty acid oxidation disorders. Biochem Biophys Res Commun 437:637-41
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Filippo, Cristina Amat di San; Ardon, Orly; Longo, Nicola (2011) Glycosylation of the OCTN2 carnitine transporter: study of natural mutations identified in patients with primary carnitine deficiency. Biochim Biophys Acta 1812:312-20
Amat di San Filippo, Cristina; Taylor, Matthew R G; Mestroni, Luisa et al. (2008) Cardiomyopathy and carnitine deficiency. Mol Genet Metab 94:162-6
Schimmenti, Lisa A; Crombez, Eric A; Schwahn, Bernd C et al. (2007) Expanded newborn screening identifies maternal primary carnitine deficiency. Mol Genet Metab 90:441-5
Longo, Nicola; Amat di San Filippo, Cristina; Pasquali, Marzia (2006) Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 142C:77-85
Hedlund, Gary L; Longo, Nicola; Pasquali, Marzia (2006) Glutaric acidemia type 1. Am J Med Genet C Semin Med Genet 142C:86-94

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