We request funding for years 21 to 25 of a program project grant entitled ~Genetic Causes of Mental Retardation~. Study of adrenoleukodystrophy (ALD), which is associated with mental retardation, was part of the original application. Eleven years ago, ALD was shown to be a peroxisomal disorder, and at about the same time it was recognized that this disease category also includes disorder such as the Zellweger syndrome, in which mental retardation is even more frequent and severe. The connection between the peroxisomal abnormality and mental retardation. Knowledge about peroxisomal disorders is advancing rapidly. They are more common and varied than had been recognized in the past. Our clinic has identified the largest number of such patients known anywhere, and during the last five years this program project grant has focused on peroxisomal disorders exclusively. The present proposal includes five projects in addition to an administrative and molecular biology core. Subproject 0009 will study phenotype-0012 genotype correlations. Subproject 0012 will examine how defects of the recently identified ALD gene cause neurological damage and mental retardation. Subprojects and 0013 will study disorders of peroxisome assembly, such as the Zellweger syndrome, which can be caused by at least eleven distinct gene defects, three of which has been defined during the last three years. Project will focus on homologues of such assembly defects in yeast, in which the biologic mechanisms can be identified rapidly, and Project 0013 will focus on human mutants. The continuum from clinical to molecular and cell biology is the central theme of this program and provides its motivation and cohesion.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
3P01HD010981-21S2
Application #
2824412
Study Section
Mental Retardation Research Committee (HDMR)
Project Start
1978-01-01
Project End
2001-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Hugo W. Moser Research Institute Kennedy Krieger
Department
Type
DUNS #
167202410
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Brose, Rebecca Deering; Shin, Gloria; McGuinness, Martina C et al. (2012) Activation of the stress proteome as a mechanism for small molecule therapeutics. Hum Mol Genet 21:4237-52
Brose, Rebecca Deering; Avramopoulos, Dimitri; Smith, Kirby D (2012) SOD2 as a potential modifier of X-linked adrenoleukodystrophy clinical phenotypes. J Neurol 259:1440-7
Steinberg, S J; Snowden, A; Braverman, N E et al. (2009) A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts. J Inherit Metab Dis 32:109-19
Moser, Hugo W; Mahmood, Asif; Raymond, Gerald V (2007) X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 3:140-51
Jia, Zhenzhen; Pei, Zhengtong; Maiguel, Dony et al. (2007) The fatty acid transport protein (FATP) family: very long chain acyl-CoA synthetases or solute carriers? J Mol Neurosci 33:25-31
Watkins, Paul A; Maiguel, Dony; Jia, Zhenzhen et al. (2007) Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J Lipid Res 48:2736-50
Jia, Zhenzhen; Moulson, Casey L; Pei, Zhengtong et al. (2007) Fatty acid transport protein 4 is the principal very long chain fatty acyl-CoA synthetase in skin fibroblasts. J Biol Chem 282:20573-83
Eichler, Florian; Mahmood, Asif; Loes, Daniel et al. (2007) Magnetic resonance imaging detection of lesion progression in adult patients with X-linked adrenoleukodystrophy. Arch Neurol 64:659-64
Lu, Jyh-Feng; Barron-Casella, Emily; Deering, Rebecca et al. (2007) The role of peroxisomal ABC transporters in the mouse adrenal gland: the loss of Abcd2 (ALDR), Not Abcd1 (ALD), causes oxidative damage. Lab Invest 87:261-72
Moser, Hugo W (2006) Therapy of X-linked adrenoleukodystrophy. NeuroRx 3:246-53

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