ABCD1 p.Gln177*
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[hide] ABCD1 mutations and the X-linked adrenoleukodystro... Hum Mutat. 2001 Dec;18(6):499-515. Kemp S, Pujol A, Waterham HR, van Geel BM, Boehm CD, Raymond GV, Cutting GR, Wanders RJ, Moser HW
ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations.
Hum Mutat. 2001 Dec;18(6):499-515., [PMID:11748843]
Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene, which encodes a peroxisomal ABC half-transporter (ALDP) involved in the import of very long-chain fatty acids (VLCFA) into the peroxisome. The disease is characterized by a striking and unpredictable variation in phenotypic expression. Phenotypes include the rapidly progressive childhood cerebral form (CCALD), the milder adult form, adrenomyeloneuropathy (AMN), and variants without neurologic involvement. There is no apparent correlation between genotype and phenotype. In males, unambiguous diagnosis can be achieved by demonstration of elevated levels of VLCFA in plasma. In 15 to 20% of obligate heterozygotes, however, test results are false-negative. Therefore, mutation analysis is the only reliable method for the identification of heterozygotes. Since most X-ALD kindreds have a unique mutation, a great number of mutations have been identified in the ABCD1 gene in the last seven years. In order to catalog and facilitate the analysis of these mutations, we have established a mutation database for X-ALD ( http://www.x-ald.nl). In this review we report a detailed analysis of all 406 X-ALD mutations currently included in the database. Also, we present 47 novel mutations. In addition, we review the various X-ALD phenotypes, the different diagnostic tools, and the need for extended family screening for the identification of new patients.
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164 X-ALD Mutations Identified in the ABCD1 Gene Allele Exon Mutation Protein Remark fs P42 1 125insC n.d. # fs P84 1 253insC n.d. # E90K 1 268G>A n.d. # S98L 1 293C>T Present S98L 1 293C>T Present R104H 1 311G>A n.d. fs A112 1 337delC Absent # R113C 1 337C>T Present # R113P 1 338G>C n.d. # Q133X 1 397C>T Absent W137X 1 411G>A Absent P143S 1 427C>T n.d. S149N 1 446G>A Present R152S 1 454C>A n.d. R152C 1 454C>T Present R152L 1 455G>T Reduced # S161P 1 481T>C n.d. # R163P 1 488G>C n.d. Y174C 1 521A>G Absent Y174C 1 521A>G n.d. Q177X 1 529C>T Absent Y181C 1 542A>G n.d. fs Y181 1 544ins8bp n.d. # Q195X 1 583C>T n.d. # T198K 1 593C>A n.d. # fs S207 1 621del664bp Absent # SV207-8insAAS 1 622-23ins9bp n.d. # K217E 1 649A>G Present # P218T 1 652C>A n.d. V224E 1 671T>G n.d. # L229P 1 686T>C n.d. L229P 1 686T>C n.d. fs S235 1 706delCGTG n.d. # W242X 1 726G>A Absent G266R 1 796G>A n.d. G266R 1 796G>A n.d. R274W, R280C 1 820C>T, 838C>T n.d. # R285P 1 854G>C n.d. S290X 1 869C>A Absent # E291del 1 871-73delGAG Absent Y296C 1 887A>G n.d. Y296C 1 887A>G n.d. fs E300 IVS1 IVS1+1g>t n.d. # fs E300 IVS1 IVS1-1g>a n.d. # S315X 2 944C>A n.d. # K336M 2 1007A>T n.d. # G343D 2 1028G>A n.d. # R401Q 3 1202G>A Present R401Q 3 1202G>A Present K407X 3 1219A>T n.d. # E427del 4 1279-81delGAA n.d. # Q430X 4 1288C>T n.d. # R464X 4 1390C>T n.d. fs E471 5 1415delAG Absent fs E471 5 1415delAG Absent fs E471 5 1415delAG Absent fs E471 5 1415delAG Absent C511X 6 1533C>A n.d. # R518Q 6 1553G>A Absent fs G528 6 1586-90del Absent # fs Y532 6 1599delG Absent # P543L 6 1628C>T Absent P543L 6 1628C>T Absent fs Q544 6 1628-34duplicated n.d. # fs R545 IVS 6 IVS6+1g>c n.d. # R554H 7 1661G>A Absent fs Q556 7 1670delTG n.d. # (continued) replaced by a pyrimidine (C or T) or vice versa, and transitions, comprising the substitution of one purine by the other, or of one pyrimidine by the other.
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ABCD1 p.Gln177* 11748843:164:527
status: NEW[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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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.
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ABCD1 p.Gln177* 21300044:99:868
status: NEW[hide] Decreased expression of ABCD4 and BG1 genes early ... Hum Mol Genet. 2005 May 15;14(10):1293-303. Epub 2005 Mar 30. Asheuer M, Bieche I, Laurendeau I, Moser A, Hainque B, Vidaud M, Aubourg P
Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy.
Hum Mol Genet. 2005 May 15;14(10):1293-303. Epub 2005 Mar 30., [PMID:15800013]
Abstract [show]
Childhood cerebral adrenoleukodystrophy (CCER), adrenomyeloneuropathy (AMN) and AMN with cerebral demyelination (AMN-C) are the main phenotypic variants of X-linked adrenoleukodystrophy (ALD). It is caused by mutations in the ABCD1 gene encoding a half-size peroxisomal transporter that has to dimerize to become functional. The biochemical hallmark of ALD is the accumulation of very-long-chain fatty acids (VLCFA) in plasma and tissues. However, there is no correlation between the ALD phenotype and the ABCD1 gene mutations or the accumulation of VLCFA in plasma and fibroblast from ALD patients. The absence of genotype-phenotype correlation suggests the existence of modifier genes. To elucidate the mechanisms underlying the phenotypic variability of ALD, we studied the expression of ABCD1, three other peroxisomal transporter genes of the same family (ABCD2, ABCD3 and ABCD4) and two VLCFA synthetase genes (VLCS and BG1) involved in VLCFA metabolism, as well as the VLCFA concentrations in the normal white matter (WM) from ALD patients with CCER, AMN-C and AMN phenotypes. This study shows that: (1) ABCD1 gene mutations leading to truncated ALD protein are unlikely to cause variation in the ALD phenotype; (2) accumulation of saturated VLCFA in normal-appearing WM correlates with ALD phenotype and (3) expression of the ABCD4 and BG1, but not of the ABCD2, ABCD3 and VLCS genes, tends to be correlated with the severity of the disease, acting early in the pathogenesis of ALD.
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76 Mutation Amino acid alteration Type of mutation at the protein level Tissue sample CCER1 521A.G Y174C Missense CCER2 1414insC fsE471 Frame shift CCER3 Unknown Unknown Unknown Fibroblast CCER4 411G.A W137X Nonsense CCER5 1961T.C L654P Missense CCER6 529C.T Q177X Nonsense CCER7 901-1G.A fsE300 Frame shift CCER8 796G.A G266R Missense CCER9 1822G.A G608S Missense Brain CCER10 1390C.A R464X Nonsense CCER11 253-254insC fsP84 Frame shift CCER12 619_627del S207_A209del Deletion AMN-C1 1414-1415insC fsE471 Frame shift AMN-C2 1661G.A R554H Missense AMN-C3 1585delG fsG528 Frame shift Fibroblast AMN-C4 1661G.A R554H Missense AMN-C5 1825G.A E609K Missense AMN-C6 919C.T Q307X Nonsense AMN-C7 1850G.A R617H Missense AMN-C8 887A.G Y296C Missense AMN-C9 965T.C L322P Missense Brain AMN-C10 1390C.T R464X Nonsense AMN-C11 [1165C.T;1224 þ 1GT.TG] [R389C;fSE408] Missense; frame shift AMN-C12 1661G.A R554H Missense AMN-C13 [1997A.C;2007C.G] [Y666S;H669Q] Missense AMN-C14 1755delG fsH586 Frame shift AMN1 529C.T Q177X Nonsense AMN2 1999C.G H667D Missense AMN3 1415delAG fsE471 Frame shift Fibroblast AMN4 337delC fsA112 Frame shift AMN5 310C.T R104C Missense AMN6 919C.T Q307X Nonsense AMN7 323C.T S108L Missense Brain All mutation designations conform to the nomenclature described by Antonarakis and den Dunnen (30,31).
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ABCD1 p.Gln177* 15800013:76:256
status: NEWX
ABCD1 p.Gln177* 15800013:76:1006
status: NEW