Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy

• Published in: Human molecular genetics Vol. 11; no. 5; pp. 499 - 505
• Main Authors: PUJOL, Aurora, HINDELANG, Colette, CALLIZOT, Noëlle, BARTSCH, Udo, SCHACHNER, Melitta, MANDEL, Jean Louis
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.03.2002; Oxford Publishing Limited (England); Oxford University Press (OUP)
• Subjects: ABCD1 gene; Adrenoleukodystrophy - etiology; Adrenoleukodystrophy - genetics; Adrenoleukodystrophy - metabolism; Adrenoleukodystrophy - pathology; Adrenomyeloneuropathy; Age of Onset; ALD gene; Animals; ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Axons - pathology; Axons - ultrastructure; Behavior, Animal; Biochemistry, Molecular Biology; Biological and medical sciences; cerebral childhood adrenoleukodystrophy; Chemokine CCL22; Chemokines, CC - genetics; Chemokines, CC - metabolism; Classical genetics, quantitative genetics, hybrids; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Gene Silencing; Genetics of eukaryotes. Biological and molecular evolution; Life Sciences; Male; Mice; Mice, Knockout; Mutation; Myelin Sheath - pathology; Myelin Sheath - ultrastructure; Neural Conduction - physiology; Phenotype; Sciatic Nerve - pathology; Sciatic Nerve - ultrastructure; Spinal Cord - pathology; Spinal Cord - ultrastructure; Vertebrata; X-linked adrenoleukodystrophy; Animal model; Vertebrata; Phenotype; Mammalia; Mouse; Rodentia; Adrenomyeloneuropathy; Peroxisome; Mutation; ABC transporter
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/11.5.499

Adrenomyeloneuropathy (AMN) and cerebral childhood adrenoleukodystrophy (CCALD) are the main phenotypic variants of an X-linked inherited metabolic disorder causing demyelination, X-linked adrenoleukodystrophy (X-ALD). It is caused by mutations in the ABCD1 (ALD) gene encoding a peroxisomal ABC transporter. Inactivation of the murine ALD gene does not lead to a detectable clinical phenotype in mice up to 6 months, and no cerebral pathology resembling the childhood form (CCALD) was observed. In this work, we show that older ALD-deficient mice exhibit an abnormal neurological and behavioral phenotype, starting at around 15 months. This is correlated with slower nerve conduction, and with myelin and axonal anomalies detectable in the spinal cord and sciatic nerve, but not in brain. The phenotype of ALD-deficient mice mimics features of human AMN, thus providing a model for investigating the pathogenesis of this disease.