TARGETED INACTIVATION OF THE X-LINKED ADRENOLEUKODYSTROPHY GENE IN MICE

In its severe form, X-linked adrenoleukodystrophy (ALD) is a lethal ne urologic disease of children, characterized by progressive cerebral de myelination and adrenal insufficiency, Associated with a biochemical d efect of peroxisomal beta-oxidation, very long-chain fatty acids (VLCF A) build up in tissues that have a high turnover of lipids, such as ce ntral nervous system (CNS) white matter, adrenal cortex, and testis, W hether the abnormal accumulation of VLCFA is the underlying cause of d emyelination or merely an associated biochemical marker is unknown, AL D is caused by mutations in the gene for a peroxisomal membrane protei n (ALDP) that shares structural features with ATP-binding-cassette (AB C) transporters, To analyze the cellular function of ALDP and to obtai n an animal model of this debilitating disease, we have generated tran sgenic mice with a targeted inactivation of the aid gene, Motor functi ons in ALDP-deficient mice developed at schedule, and unexpectedly, ad ult animals appeared unaffected by neurologic symptoms up to at least 6 months of age, Biochemical analyses demonstrated impaired beta-oxida tion in mutant fibroblasts and abnormal accumulation of VLCFAs in the CNS and kidney, In 6-month-old mutants, adrenal cortex cells displayed a ballooned morphology and needle-like lipid inclusions, also found i n testis and ovaries, However, lipid inclusions and demyelinating lesi ons in the CNS were not a feature, Thus, complete absence of ALDP expr ession results in a VLCFA storage disease but does not impair CNS func tion of young adult mice by pathologic and clinical criteria. This sug gests that additional genetic or environmental conditions must be fulf illed to model the early-onset and lethality of cerebral ALD in transg enic mice. (C) 1997 Wiley-Liss, Inc.