Determination of 30 X-linked adrenoleukodystrophy mutations, including 15 not previously described

Lachtermacher, M.B.R.; Seuánez, Héctor N.; Moser, Ann B.; Moser, Hugo W.; Smith, Kirby D.

doi:10.1002/(sici)1098-1004(200004)15:4<348::aid-humu7>3.0.co;2-n

Cited by 30 publications

(3 citation statements)

References 14 publications

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“…Although reverse transcription (RT)-PCR has been preferentially used for the analysis of ABCD1 gene [11, 12, 26] to overcome the difficulty of specifically amplifying the ABCD1 gene owing to the existence of the related highly homologous genes [13, 27], primers allowing the specific amplification of ABCD1 enable the PCR analysis of genomic DNA, which is much easier than RT-PCR analysis. Similar approaches have also been used for SSCP-based [13, 28] and DNA-based diagnostic testing methods [29].…”

Section: Discussionmentioning

confidence: 99%

Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes

et al. 2010

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Adrenoleukodystrophy (ALD) is an X-linked disorder affecting primarily the white matter of the central nervous system occasionally accompanied by adrenal insufficiency. Despite the discovery of the causative gene, ABCD1, no clear genotype–phenotype correlations have been established. Association studies based on single nucleotide polymorphisms (SNPs) identified by comprehensive resequencing of genes related to ABCD1 may reveal genes modifying ALD phenotypes. We analyzed 40 Japanese patients with ALD. ABCD1 and ABCD2 were analyzed using a newly developed microarray-based resequencing system. ABCD3 and ABCD4 were analyzed by direct nucleotide sequence analysis. Replication studies were conducted on an independent French ALD cohort with extreme phenotypes. All the mutations of ABCD1 were identified, and there was no correlation between the genotypes and phenotypes of ALD. SNPs identified by the comprehensive resequencing of ABCD2, ABCD3, and ABCD4 were used for association studies. There were no significant associations between these SNPs and ALD phenotypes, except for the five SNPs of ABCD4, which are in complete disequilibrium in the Japanese population. These five SNPs were significantly less frequently represented in patients with adrenomyeloneuropathy (AMN) than in controls in the Japanese population (p = 0.0468), whereas there were no significant differences in patients with childhood cerebral ALD (CCALD). The replication study employing these five SNPs on an independent French ALD cohort, however, showed no significant associations with CCALD or pure AMN. This study showed that ABCD2, ABCD3, and ABCD4 are less likely the disease-modifying genes, necessitating further studies to identify genes modifying ALD phenotypes.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-010-0253-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes

et al. 2010

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“… Summary of the reported mutation sites and clinical manifestations from the database of UniProt ( https://www.uniprot.org/uniprot/ ) and reported references [ 22 – 35 ]. The clinical types include childhood and adolescent cerebral ALD (CCALD and adoles ALD), adult ALD, AMN (adrenomyeloneuropathy), adrenal insufficiency-only (AIO), complicated ALD which cannot be classified, and asymptomatic or presymptomatic types.…”

Section: Figurementioning

confidence: 99%

Identification of Two Novel Mutations of ABCD1 Gene in Pedigrees with X-Linked Adrenoleukodystrophy and Review of the Literature

Dong

et al. 2022

International Journal of Endocrinology

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Background. X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal metabolism disorder, resulting from the loss-of-function mutation of ATP-binding cassette protein subfamily D1 (ABCD1) gene. The dysfunction of ALD protein, a peroxisomal ATP-binding cassette transporter, results in the excessive saturated very long-chain fatty acids (VLCFAs) accumulation in organs including the brain, spine, and adrenal cortex. X-ALD is characterized as the childhood, adolescent, adult cerebral ALD, adrenomyeloneuropathy (AMN), adrenal insufficiency, and asymptomatic phenotypes, exhibiting a high variety of clinical neurological manifestations with or without adrenocortical insufficiency. Results. In this study, we reported two cases of X-ALD, which were first diagnosed as adrenal insufficiency (Addison’s disease) and treated with adrenocortical supplement. However, both of the cases progressed as neurological symptoms and signs after decades. Elevated VLCFAs level, brain MRI scan, and genetic analysis confirmed final diagnosis. In addition, we identified two novel mutations of ABCD1 gene, NM_000033.3 (ABCD1): c.874_876delGAG (p.Glu292del) and NM_000033.3 (ABCD1): c.96_97delCT (p.Tyr33Profs ∗ 161), in exon 1 of ABCD1 gene. Sanger sequencing confirmed that the proband’s mother of the first case was heterozygous carrying the same variant. Adrenal insufficiency-only type is very rare; however, it may be the starting performance of X-ALD. In addition, we summarized reported mutation sites and clinical manifestations to investigate the correlationship of phenotype-genotype of X-ALD. Conclusions. The early warning manifestations should be noticed, and the probability of X-ALD should be considered. This report could be beneficial for the early diagnosis and genetic counseling for patients with X-ALD.

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“…Published phenotypes: f 1415-1416/del/AG: ccALD, adult cALD, AMN, Addison, asymptomatic [Barcelo et al, 1994;Fuchs et al, 1994;Kemp et al, 1994;Kok et al, 1995;Lachtermacher et al, 2000;Ligtenberg et al, 1995]. g S98L: ccALD, asymptomatic [Feigenbaum et al, 1996].…”

Section: Subjectsmentioning

confidence: 99%

Eight novelABCD1gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: The first polymorphism causing an amino acid exchange

Dvořáková¹,

Štorkánová²,

Unterrainer

et al. 2001

Hum. Mutat.

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X-ALD is a neurological disorder associated with inherited defects in the ABCD1 (ALD) gene located on Xq28 and with impaired peroxisomal very long-chain 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 cDNA or genomic PCR products. In 10 families there were 10 different mutations, eight of which were novel. The spectrum of mutations consists of six point mutations, three microdeletions (1bp, 2bp, 4 bp), and one large deletion (229bp). In the 11th family we detected two novel single-base pair substitutions in exon 1 (c.38 A>C and c.649 A>G), both causing amino acid exchanges (N13T and K217E). Expression studies revealed that only K217E is a deleterious mutation, because a plasmid encoding ALDP with K217E was ineffective in the restoration of defective beta-oxidation in X-ALD fibroblasts. The N13T amino acid exchange, on the other hand, did not affect ALDP function. Thus, 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-wide, it seems to be very rare or unique. Two additional novel polymorphisms were 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 frequencies of these two polymorphisms, were 11/150 and 2/150 control alleles, respectively.

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Determination of 30 X-linked adrenoleukodystrophy mutations, including 15 not previously described

Cited by 30 publications

References 14 publications

Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes

Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes

Identification of Two Novel Mutations of ABCD1 Gene in Pedigrees with X-Linked Adrenoleukodystrophy and Review of the Literature

Eight novelABCD1gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: The first polymorphism causing an amino acid exchange

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