ABCMdb

ABCD1 p.Arg259Trp

Predicted by SNAP2:	A: D (66%), C: D (71%), D: D (91%), E: D (85%), F: D (80%), G: D (80%), H: D (63%), I: D (75%), K: N (72%), L: D (75%), M: D (71%), N: D (71%), P: D (91%), Q: D (66%), S: D (75%), T: D (66%), V: D (75%), W: D (85%), Y: D (80%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Molecular diagnosis of X-linked adrenoleukodystrop... Clin Chim Acta. 2011 May 12;412(11-12):970-4. Epub 2011 Feb 12. Lan F, Wang Z, Xie H, Huang L, Ke L, Yang B, Zhu Z
Molecular diagnosis of X-linked adrenoleukodystrophy: experience from a clinical genetic laboratory in mainland China with report of 13 novel mutations.
Clin Chim Acta. 2011 May 12;412(11-12):970-4. Epub 2011 Feb 12., [PMID:21300044]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by progressive demyelination of the nervous system, adrenocortical insufficiency and increase of very long chain fatty acids (VLCFAs) in the plasma and tissues. METHODS: A total of 131 individuals from 30 Chinese pedigrees were involved in this study, including 42 symptomatic patients, 44 female carriers, and 15 high-risk fetuses from 13 families. The mutation was first pinpointed through long distance RT-PCR-based RNA approach and confirmed through peripheral blood DNA approach. RESULTS: A total of 28 mutations were identified, of which 19 were missense, 3 nonsense and 6 frame-shift mutations. Thirteen mutations were novel, i.e. p.R280L, p.P580L, p.G343V, p.S108X, p.R259W, p.P534R, p.fs A246, p.L576P, p.K602X, p.A314P, p.N148D, p.H283R, and p.fs R89. Two mutations occurred de novo, for they were not found in somatic cells of their parents. Three females from the same family developed AMN-like symptoms and they were heterozygous for the p.H283R mutation. Four asymptomatic boys were diagnosed as X-ALD patients and prenatal molecular diagnosis were provided for 13 X-ALD-stricken families. CONCLUSIONS: Our work extended the spectrum of mutations in X-ALD and benefited genetic counseling through reliable identification of heterozygous females and asymptomatic males.

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No. Sentence Comment
4 Thirteen mutations were novel, i.e. p.R280L, p.P580L, p.G343V, p.S108X, p.R259W, p.P534R, p.fs A246, p.L576P, p.K602X, p.A314P, p.N148D, p.H283R, and p.fs R89. Login to comment
53 Thirteen mutations were novel, i.e. p.R280L, p.P580L, p.G343V, p.S108X, p.R259W, p.fs A246, p.L576P, p.P534R, p.K602X, p.A314P, p.N148D, p.H283R, and p.fs R89, 9 of which were missense mutations. Login to comment
56 The mutations p.S108X and p.R259W occurred simultaneously in the same family and they lined tandemly on the same allele of ABCD1 gene, a phenomenon called multiple mutations. Login to comment
82 Two sets of multiple mutations, i.e. [p.S108X; p.R259W] and [p.K217E; p. V489V], were identified, which were new according to the international database (http://www.x-ald.nl), and it was the first time that multiple mutations were found in the ABCD1 gene in Chinese population. Login to comment
99 Pedigree Number of patient Number of carriere Phenotype of patient Base change Amino acid change Position of mutation Feature of mutation Prenatal diagnosis 1 1 2 AdolCALD 1225GNT R280L Exon 1 Missense 2 1 1 CCALD 1909CNT P508L Exon 6 Missense 3 4 3 CCALD 1987CNG P534R Exon 6 Missense Y 4 1 1 CCALD 1182GNA G266R Exon 1 Missense 5 1a +1b 1 CCALD 2235CNG R617G Exon 8 Missense Y 6 1+1a +1c 1 CCALD 1414GNT G343V Exon 2 Missense 7 1 1 CCALD 1415_02 del AG fs E471 Exon 5 Frameshift 8 1+1b 1 CCALD 2235CNT R617C Exon 8 Missense Yh 9 1 1 CCALD 2065CNT P560L Exon 7 Y 10 1+1a 2+1b CCALD [709 NA; 1161CNT] [S108X; R259W] Exon 1 Nonsense; Missense Y 11 1 1 CCALD 1126ins GCCATCG fs I246 Exon 1 Frameshift 12 1 1 CCALD 2113TNC L576P Exon 7 Missense 13 1a +2c 3 CCALD 807GNA A141T Exon 1 Missense 14 1 1 CCALD 1415_02 del AG fs E471 Exon 5 Frameshift Y 15 1 1+1b CCALD 915CNA Q177X Exon 1 Nonsense Yh 16 1+1a 1 CCALD 1588GNA R401Q Exon 3 Missense 17 1 1 CCALD 1212 ANG K276E Exon 1 Missense Y 18 1 1 CCALD 907 ANG Y174C Exon 1 Missense 19 1 2 CCALD 2190 ANT K602X Exon 8 Nonsense 20 1 1 CCALD 1326GNC A314P Exon 2 Missense 21 1 1 CCALD 828 ANG N148D Exon 1 Missense Y 22 1 1 CCALD 1588GNA R401Q Exon 3 Missense Y 23 1 0f CCALD 2278GNA C631Y Exon 9 Missense 24 1a 1 CCALD 1008insG fs S207 Exon 1 Frameshift Y 25 1 0f CCALD 1920GNA G512S Exon 6 Missense 26 1+1c 3 CCALD 1415_02 del AG fs E471 Exon 5 Frameshift Y 27 1+1b 1 CCALD [1035ANG; 1853GNA] [K217E; V489V] Exon 1 Missense; same sense Y 28 1+3d 4 AMNg 1234ANG H283R Exon 1 Missense 29 1+2a 3 CCALD 1233CNG H283D Exon 1 Missense 30 2 3 AMN; CCALD 656_57 delGA fs R89 Exon 1 Frameshift a patient or proband died at the time of referral; b fetus by prenatal diagnosis; c presymptomatic at the time of referral; d female heterozygote patient; e determined by molecular ananlysis or deduced by the fact that the carrier was the daughter of an X-ALD, or the mother of at least one X-ALD patients; f de novo mutation; g including three heterozygote female patients; h twice for two pregnancies. Login to comment

[hide] Two novel multiple mutations in chinese patients w... Neuropediatrics. 2010 Jun;41(3):151-3. Epub 2010 Sep 21. Ke LF, Wang ZH, Huang LH, Xie HH, Lan FH
Two novel multiple mutations in chinese patients with adrenoleukodystrophy.
Neuropediatrics. 2010 Jun;41(3):151-3. Epub 2010 Sep 21., [PMID:20859837]

Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by mutations in the ABCD1 gene. Up to now, more than 1 050 mutations have been reported in the ABCD1 gene, of which only 10 are multiple mutations in one allele of the gene. In this study, we report 2 novel multiple mutations in 2 patients with X-ALD from 2 unrelated Chinese families. Total RNA and genomic DNA were isolated from peripheral blood of the 2 patients, and the ABCD1 gene was analyzed by direct sequencing and denaturing high-performance liquid chromatography. We detected [p.Ser108X+p.Arg259Trp] in patient 1, [p.Lys217Glu+p.Val489Val] in patient 2 in one allele of the ABCD1 gene. Both novel multiple mutations have not previously been reported and this is the first report of multiple mutations identified in Chinese patients with X-ALD.

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32 Fragments that covered the p.Ser108X and p.Arg259Trp mutations (pedigree 1) or p.Lys217Glu and p.Val489Val mutations (pedigree 2) of the ABCD1 gene were amplified with the primers listed in●▶ Table 1 [7]. Login to comment
37 323C>A and c.775C>T) lined tandemly were detected in one allele of the ABCD1 gene, leading to the substitution of the normal serine with stop codon at codon 108 (p.Ser108X) and the substitution of the normal arginine with tryptophan at codon 259 (p.Arg259Trp). Login to comment
61 The second missense mutation (p.Arg259Trp) has not been reported previously. Login to comment
66 Fourthly, the in silico analysis of pathogenicity was performed using PolyPhen, and the prediction result revealed that p.Arg259Trp is probably damaging, suggesting that the mutation is pathogenic. Login to comment
67 For the multiple mutation combination p.Ser108X and p.Arg259Trp, it is rather obvious that the nonsense mutation is disease-causing by itself, as it results in no ALDP. Login to comment

[hide] A rapid and sensitive protocol for prenatal molecu... Clin Chim Acta. 2010 Dec 14;411(23-24):1992-7. Epub 2010 Aug 26. Lan F, Wang Z, Ke L, Xie H, Huang L, Huang H, Tu X, Zheng D, Zeng J, Li H, Xin N, Yang B
A rapid and sensitive protocol for prenatal molecular diagnosis of X-linked adrenoleukodystrophy.
Clin Chim Acta. 2010 Dec 14;411(23-24):1992-7. Epub 2010 Aug 26., [PMID:20800589]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative genetic disease characterized by progressive demylination of the brain, adrenal insufficiency and elevated VLCFA level. ABCD1gene is the disease gene and more than 500 unique mutations in the ABCD1gene have been recorded in the database, approximately 60% of which are noncurrent ones. Although great progress has been made in the treatment of X-ALD, prenatal diagnosis is still badly needed by X-ALD-stricken families. METHODS: Twelve high-risk fetuses entered this study. Amniotic fluid (AF) was divided into two parts, with one part being used directly to isolate genomic DNA and debris from the other part for amniotic fluid cells (AFC) culturing. STR profiling was performed to evaluate maternal contamination of AFC genomic DNA. Two different molecular approaches, be they any two of direct sequencing, PCR-RFLP, ARMS, dot hybridization and DHPLC, were applied to determine whether the mutation identified in the index patient was found in the fetus. RESULTS: The genotypes of all 12 fetuses were determined, among which 2 were diagnosed as ALD males, 5 unaffected males, 1 heterozygote, and 4 normal unaffected females. A total of 9 families sent samples of umbilical blood at the time of delivery, and results of molecular checking of these samples agreed with those of prenatal diagnosis. Up until now, no ALD-related abnormalities were reported postnatally. CONCLUSION: An in-house protocol for the prenatal molecular diagnosis of X-ALD was established, and this protocol would provide accurate and rapid prenatal genetic service to X-ALD-stricken families.

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43 One proband carried a frameshift mutation (c.1415_16delAG) and the remaining one had two mutations (p.Ser108X and p.Arg259Trp) on the same allele. Login to comment
74 Family Origin (province) Genotype of proband Age (years) of carrier at amniocentesis Weeks of pregnancy at amniocentesis 1 Guangdong p.Arg617Gly 39 28 2 Shandong p.Pro534Arg 25 21 3 Fujian p.Arg617Cys 33(34)a 16(17)a 4 Hebei 1415_1416delAG (p.Glu471fs) 29 26 5 Fujian [p.Ser108X; p.Arg259Trp] 33 19 6 Shandong p.Pro560Leu 35 18 7 Anhui p.Gln177X 33 20 8 Shandong p.Lys276Glu 33 16 9 Hubei p.Asn148Asp 35 18 10 Jilin c.622_623insG (p.Ser207fs) 35 16 11 Guangxi p.Arg401Gln 32 16 a Figures in parentheses represent those data of second-time prenatal diagnosis for another fetus from family 3. Login to comment
167 Fetus Family Methods Sex Genotype Diagnosis 1 1 Dot hybridization+ARMS Male p.Arg617Gly ALD hemizygote 2 2 PCR-RFLP+sequencing Male No mutation Normal hemizygote 3 3 DHPLC+sequencing Female No mutation Normal homozygote 4 3 PCR-RFLP+sequencing Male p.Arg617Cys ALD hemizygote 5 4 DHPLC+sequencing Male No mutation Normal hemizygote 6 5 DHPLC+sequencing Female [p.Ser108X; p.Arg259Trp]/ no mutation ALD heterozygote 7 6 PCR-RFLP+sequencing Female No mutation Normal homozygote 8 7 DHPLC+sequencing Female No mutation Normal homozygote 9 8 DHPLC+sequencing Male No mutation Normal hemizygote 10 9 PCR-RFLP+sequencing Male No mutation Normal hemizygote 11 10 DHPLC+sequencing Male No mutation Normal hemizygote 12 11 PCR-RFLP+sequencing Female No mutation Normal homozygote based on molecular techniques. Login to comment