Identification of a Two Base Pair Deletion in Five Unrelated Families with Adrenoleukodystrophy: A Possible Hot Spot for Mutations

Two intronic mutations in the adrenoleukodystrophy gene

“…The ALDP belongs to the ATP-binding cassette (ABC) superfamily of transporter proteins, indicating that the primary defect in ALD interferes with a transport process essential for 3-oxidation of VLCFA. So far, few chromosomal deletions Car tier et al, 1993) and two exonic point mutations (Cartier et alM 1993;Uchiyama et al, 1994) were reported, and a possible hot spot for mutations was identified in the fifth exon of the ALD gene (Kemp et aL, 1994). We report two patients from two Dutch kindreds with mutations in introns of the ALD gene, leading to the use of novel or cryp tic 3' splice acceptor sites and prematurely termi nated proteins.…”

“…Total chromosomal DNA and mRNA were iso lated from fibroblasts, according to standard pro cedures. PCR and sequencing was performed as described (Kemp et al, 1994;Ligtenberg et al, 1995).…”

Novel missense and frameshift mutations in the adrenoleukodystrophy gene

“…Ib), which causes premature termination of translation at nucleotides 2048-2050 (TGA), resulting in the elimination of one of the two ATP-binding cassettes (corresponding to nucleotides 2235-2276). Twenty-seven ALD cases have been suggested to be caused by frameshift mutations (Kemp et al, 1994;Ligtenberg et al, 1995;Braun et al, 1995;Song et al, 1995;Fanen et al, 1994;Barcel6 et al, 1994;Fuchs et al, 1994;Kok et al, 1995;Krasemann et al, 1996), more than a half of them being the same defect (1801delAG), but the mutation we found has never been reported. The patient's mother is heterozygous for this site and his younger brother (S.A.) has the same deletion (Fig.…”

Mutations in the adrenoleukodystrophy gene

“…Second, a dinucleotide deletion at nucleotide position 1801-1802 in exon 5 has been observed in seven separate studies and in a total of 14 different kindreds (Table 1). This microdeletion is the most frequent of all mutations found in the ALD gene and appears to represent a mutation hotspot Barceló et al, 1994;Kemp et al, 1994;Fuchs et al, 1994;Ligtenberg et al, 1995;Krasemann et al, 1996;Feigenbaum et al, 1996). Analysis of these kindreds has revealed differing haplotypes, which suggests the absence of a founder effect .…”

“…Table 1 summarises the current literature of ALD gene mutations and indicates molecular and clinical information about each mutation. Approximately 50% of mutations described to date are missense mutations, with the remainder nonsense mutations leading to premature termination of translation (12/110) Uchiyama et al, 1994;Fanen et al, 1994;Fuchs et al, 1994;Braun et al, 1995;Kok et al, 1995;Watkins et al, 1995;Rowland et al, 1996;Krasemann et al, 1996;Feigenbaum et al, 1996), microdeletions (18/110) Kemp et al, 1994;Barceló et al, 1994;Fuchs et al, 1994;Kok et al, 1994;Fanen et al, 1994;Song et al, 1995;Braun et al, 1995;Krasemann et al, 1996;Feigenbaum et al, 1996), microinsertions (3/110) (Krasemann et al, 1996;Feigenbaum et al, 1996), amino acid deletions (4/ 110) (Koike et al, 1994;Ligtenberg et al, 1995;Braun et al, 1995;Watkins et al, 1995;Krasemann et al, 1996), amino acid insertions (2/110) (Krasemann et al, 1996;Feigenbaum et al, 1996), and missense mutations leading to RNA splice site defects (5/110) Fanen et al, 1994;Feigenbaum et al, 1996). One "samesense" mutation has been documented (Fanen et al, 1994;Fuchs et al, 1994), which has been suggested as an alternate sequence or silent polymorphism.…”