Kirby Smith, Ph.D.
The Genetic Basis for Phenotypic Variability of Inherited Metabolic Diseases; Molecular Biology of the Peroxisome
The severity of adult hemoglobinopathies can be moderated by the presence of red cells containing fetal hemoglobin (F-cells). The fraction of F-cells in adults varies over a 20 fold range. We have identified a locus (FCP) on the X-chromosome that accounts for 50% of this variation. The FCP gene has been mapped to a small (<1Mb) region of Xp and its physical isolation is in progress.
X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder with variable phenotypic expression that is characterized by elevated very long chain fatty acids. However, the product of the gene defective in X-ALD (ALDP) is a membrane transporter and is not related to enzymes that activate or oxidize fatty acids. Using genetic anlyses, we have identified an autosomal gene that in part determines the phenotypic expression of X-ALD. We are examining the function of ALDP, determining the underlying pathophysiology of the various forms of X-ALD, searching for the autosomal modifying gene and investigating the possibility of pharmcological gene therapy for peroxisomal disorders.
1. McGuinness MC, Wei H-M, Smith KD, 2000. Therapeutic developments in peroxisome biogenesis disorders. Exp Opin Invest Drugs 9: 1985-1992.
2. Bezman L, Moser A, Raymond G, Rinaldo P, Watkins P, Smith K, Kass N, Moser H, 2001. Adrenoleukodystrophy: Incidence, new mutation rate and results of extended family screening. Ann Neurol. 49:512-517.
3. Chang YC, Littera R, Garau K, Smith KD, Dover GJ, Iannelli S, Cacace E, Contu L, 2001. The Role ofHetero-cellular Hereditary Persistence of Fetal Hemoglobin in beta-thalassemia Intermedia. Brit J Haematol114:899-906.
4. Ito M, Blumberg BM, Mock DJ, Goodman AD, Moser AB, Moser HW, Smith KD, Powers JM, 2001. PotentialEnviromental and Host Participants in the Early White Matter Lesion of Adrenoleukodystrophy: Morphologic Evidence for CD8 Cytotoxic T Cells, Cytolysis of Oligodendrocytes and CD1-Mediated Lipid Antigen Presentation. Neuropath and Exp Neurol 60:1004-1019.
5. McGuinness, MC, Zhang H-P, Smith KD, 2001. Evaluation of pharmacological induction of fatty acid ß-oxidation in X-linked adrenoleukodystrophy. Mol. Genet Metab 74,256-263.
6. Chang YP, Littera R, Garau R, Smith KD, Dover GJ, Iannelli S, Cacace E, Contu L, 2001. The role of heterocellular hereditary persistence of fetal haemoglobin in beta(0) thalassaemia intermedia. Brit J Haematol 114:899- 906.
7. Heinzer AK, Kemp S, Lu JF, Watkins PA, Smith KD, 2002. Mouse very long-chain acyl- CoA synthetase in X-inked adrenoleukodystrophy. J Biol Chem 277:28765-73.
8. Li X, Baumgart E, Dong GX, Morrell JC, Jimenez-Sanchez G, Valle D, Smith KD, Gould SJ, 2002. PEX11 alpha is required for peroxisome proliferation in response to 4-phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor alpha-mediated peroxisome proliferation. Mol Cell Biol 22:8226-40. PMC134051
9. McGuiness MC, Lu JF, Zhang HP, Dong GX, Heinzer AK, Watkins PA, Powers J, Smith KD, 2003. Role of ALDP (ABCD1) and Mitochondria in X-Linked Adrenoleukodystrophy. Mol Cell Biol 23:744-53. PMC151532 10. Heinzer AK, McGuinness MC, Lu JF, Stine CO, Wei H, van der Vlies M, Dong GX, Powers J, Watkins PA ,Smith KD. 2003. Mouse models and genetic modifiers in X-linked adrenoleukodystrophy. Adv. Exp. Med. Biol. 544:75-93
11. Heinzer AK, Watkins PA, Lu JF, Kemp S, Moser AB, Li YY, Mihalik S, Powers JM, Smith KD. 2003. A very
long-chain acyl-CoA synthetase-deficient mouse and its relevance to X-linked adrenoleukodystrophy. Hum Mol Genet 12:1145-1154.
12. Pei Z, Oey NA, Zuidervaart MM, Jia Z, Li Y, Steinberg SJ, Smith KD, Watkins PA. The acyl-CoA synthetase "bubblegum" (lipidosin): further characterization and role in neuronal fatty acid beta-oxidation. J Biol Chem. 2004, 278(47):47070-8.
13. Jia Z, Pei Z, Li YY, Wei L, Smith KD, Watkins, PA. 2004, X-linked adrenoleukodystrophy: role of very long chain acyl-CoA synthetases. Mol Gen and Metabolism 83:117-127
14. Powers JM, Zhengtong P, Heinzer AK, Deering R, Moser AB, Moser HW, Watkins PA, Smith KD. 2005. Adreno-leukodystrophy: Oxidative Stress Of Mice and Men. J. Neuropath and Exptl.Neurology. 64:1067-1079
15. Lu J-F, Barron-Casella E, Deering E, Heinzer AK, Moser AB, deMesy Bentley KL, Wand GS, McGuiness M, Pei Z,Watkins PA, Pujol A, Smith KD, Powers JD, 2007. The Role of Peroxisomal ABC Transporters in the Mouse Adrenal Gland: The loss of Abcd2 (ALDR), Not Abcd1 (ALD), Causes Oxidative Damage. Laboratory Inves. 87:261-272.
Kirby Smith, Ph.D.
Institute for Genetic Medicine
Johns Hopkins University
School of Medicine
733 N. Broadway
BRB Suite 419
Baltimore, Maryland 21205