Eight novel ABCD1 gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: The first polymorphism causing an amino acidexchange

X-ALD is a neurological disorder associated with inherited defects in the A BCD1 (ALD) gene located on Xq28 and with impaired peroxisomal very long-cha in fatty acid beta -oxidation. We examined the ABCD1 gene in probands from 11 unrelated X-ALD Czech and Slovak families by the direct sequencing of cD NA or genomic PCR products. In 10 families there were 10 different mutation s, eight of which were novel. The spectrum of mutations consists of six poi nt mutations, three microdeletions (1bp, 2bp, 4 bp), and one large deletion (229bp). In the 11th family we detected two novel single-base pair substit utions in exon 1 (c.38 A>C and c.649 A>G), both causing amino acid exchange s (N13T and K217E). Expression studies revealed that only K217E is a delete rious mutation, because a plasmid encoding ALDP with K217E was ineffective in the restoration of defective beta -oxidation in X-ALD fibroblasts. The N 13T amino acid exchange, on the other hand, did not affect ALDP function. T hus, N13T represents the first polymorphism causing an amino acid exchange in the ABCD1 gene. As this polymorphism was observed neither in 100 control alleles nor in 300 X-ALD patients who have been sequenced so far world-wid e, it seems to be veri rare or unique. Two additional novel polymorphisms w ere found by the sequencing of the ABCD1 gene from our patients: c.-59 C/T in the 5'untranslated region and c.2019 C/T (F673F) in exon 10. The frequen cies of these two polymorphisms, were 11/150 and 2/150 control alleles, res pectively. Hum Mutat 18:52-60, 2001, (C) 2001 Wiley-Liss. Inc.