ABCD3 p.Gln590*
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[hide] X-linked adrenoleukodystrophy: genes, mutations, a... Neurochem Res. 1999 Apr;24(4):521-35. Smith KD, Kemp S, Braiterman LT, Lu JF, Wei HM, Geraghty M, Stetten G, Bergin JS, Pevsner J, Watkins PA
X-linked adrenoleukodystrophy: genes, mutations, and phenotypes.
Neurochem Res. 1999 Apr;24(4):521-35., [PMID:10227685]
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X-linked adrenoleukodystrophy (X-ALD) is a complex and perplexing neurodegenerative disorder. The metabolic abnormality, elevated levels of very long-chain fatty acids in tissues and plasma, and the biochemical defect, reduced peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity, are ubiquitous features of the disease. However, clinical manifestations are highly variable with regard to time of onset, site of initial pathology and rate of progression. In addition, the abnormal gene in X-ALD is not the gene for VLCS. Rather, it encodes a peroxisomal membrane protein with homology to the ATP-binding cassette (ABC) transmembrane transporter superfamily of proteins. The X-ALD protein (ALDP) is closely related to three other peroxisomal membrane ABC proteins. In this report we summarize all known X-ALD mutations and establish the lack of an X-ALD genotype/phenotype correlation. We compare the evolutionary relationships among peroxisomal ABC proteins, demonstrate that ALDP forms homodimers with itself and heterodimers with other peroxisomal ABC proteins and present cDNA complementation studies suggesting that the peroxisomal ABC proteins have overlapping functions. We also establish that there are at least two peroxisomal VLCS activities, one that is ALDP dependent and one that is ALDP independent. Finally, we discuss variable expression of the peroxisomal ABC proteins and ALDP independent VLCS in relation to the variable clinical presentations of X-ALD.
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103 As suggested by the obser- al. Table I. X-linked Adrenoleukodystrophy World Wide Mutations (9/98) Exon 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 3 3 3 3 4 5 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 8 8 8 Allele S98L R104C R104H T105I L107P S108W G116R A141T N148S S149N R152C R152P R163H Y174D Y174S Q178E Y181C R182P D194H D200N D200V L211P N214D L220P D221G T254M P263L G266R E271K K276E G277R G277W E291K E291D A294T Y296C E302K L322P S342P R389G R389H R401W R401Q R418W P484R G507V G512S S515F R518W R518Q G522W P534L F540S Q544R S552P R554H P560L P560R M566K R591W R591Q S606P S606L E609K Mutation 293C>T 310C>T 311G>A 3 HOT 320T>C 323C>G 346G>A 421G>A 443A>G 446G>A 454OT 455G>C 488G>A 520T>G 521A>C 5320G 542A>G 545G>C 580G>C 598OA 599A>T 632T>C 640A>G 659T>C 662A>G 761OT 788OT 796G>A 811G>A 826A>G 829G>A 829G>T 871G>A 873OC 880G>A 887A>G 904G>A 965T>C 1024T>C 11650G 1166G>A 1201OT 1202G>A 1252OT 1452OG 1520G>T 1534G>A 1544OT 1552OT 1553G>A 1564G>A 1601OT 1619T>C 1631A>G 1654T>C 1661G>A 16790T 1679OG 1697T>A 1771OT 1772G>A 1816T>C 1817OT 1825G>A Missense muta ATG(387) 679OT 696OT 697G>A 700OT 706T>C 709OG 732G>A 807G>A 829A>G 832G>A 840OT 841G>C 874G>A 906T>G 907A>C 918OG 928A>G 931G>C 966G>C 984G>A 985A>T 1018T>C 1026A>G 1045T>C 1048A>G 1147C>T 1174C>T 1182C>A 1197G>A 1212A>G 1215G>A 1215G>T 1257G>A 1259G>C 1266G>A 1273A>G 1290G>A 1351T>C 1410T>C 1551C>G 1552G>A 1587OT 1588G>A 1638OT 1838OG 1906G>T 1920G>A 1930OT 1938OT 1939G>A 1950G>A 1987OT 2005T>C 2017A>G 2040T>C 2047G>A 20650T 20650C>G 2083T>A 2157C>T 2158G>A 2202T>C 2203OT 2211G>A ions N 2 2 1 1 1 1 1 1 3 1 2 1 1 2 1 1 1 I 1 1 1 1 1 1 1 1 1 3 1 1 1 1 1 1 1 1 1 1 1 1 2 1 3 3 1 1 3 1 3 2 1 1 1 2 1 1 6 1 1 1 1 1 3 2 ALDP + +/- nd - nd +/- - nd + + + nd nd nd nd nd nd nd + nd nd nd nd +/- - nd +/- nd nd + nd nd nd - nd nd nd nd + nd + nd + - nd nd - nd +/- - - - nd + - - +/- - - nd + - + - Reference 36 31,32 29 36 37 36 36 31 24,36,73 32 31,36 32 32 24,37 72 29 36 31 32 73 36 37 73 32 36 37 36 24,32,73 73 13 37 31 14 13 36 73 38 41 13 37 31,32 73 24,37,73 24,37,* 28 73 31,35,36 24 23,36 39,73 36 35 73 39,73 * * 29,36,73 36 31 73 31 36 23,31,73 32,37 Total 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 525X-ALD: Genes, Mutations, and Phenotypes Table I. Continued. Exon 8 8 8 8 9 9 9 10 Exon 1 1 1 1 1 1 1 2 2 4 4 5 7 8 9 10 Exon 1 1 1 1 5 6 7 9 Exon 3 6 7 7 9 Exon 1 1 1 1 1 1 1 1 1 1 1 1 1 3 Allele E609G R617C R617G R617H A626T D629H R660W W679R Allele W10X Q133X W137X Q157X Y181X Y212X W242X Q311X W326X R464X Q466X E477X Q590X W595X Q645X Q672X Allele 80-81insLRL 138-141del 277-278insN E291del 491-500insV G528del 587-590del I657del Allele Fs E408 Fs R545 Fs R545 Fs G593 Fs R622 Allele Fs A19 FsP34 FsL46 FsT91 FsG92 Fs A99 Fs Q133 Fs Y180 Fs L197 Fs S207 FsR231 Fs F261 Fs G266 Fs V378 Mutation 1826A>G 1849C>T 1849C>G 1850G>A 1876G>A 1885G>C 1978C>T 2035T>C Mutation 30G>A 397C>T 411G>A 469C>T 543C>A 636C>G 726G>A 931C>T 977G>A 1390C>T 1396C>T 1429G>T 1768C>T 1785G>A 1933C>T 2014C>T In frame 871delGAG 1582delGGT 1759-70del 1969delATC Mutation 1224A>G ivs1634+1G>A ivs1635-2A>G ivs1780+1G>A ivs1866-10G>A Mutation 56delC 102C>AT 138insT 274del34 277delC 298delG 401TGCTG>AGCATT 541delTA 591insT 618dell3 693delGG 785del7 796delG 1135insC Missense mutations ATG(387) 2212A>G 2235C>T 2235C>G 2236G>A 2262G>A 2271G>C 2364C>T 2421T>C Nonsense mutations 416G>A 783C>T 797G>A 855C>T 929C>A 1022C>G 1112G>A 1317C>T 1363G>A 1776C>T 1782C>T 1815G>T 2154C>T 2171G>A 2319C>T 2400C>T amino acid insertions & deletions 1257delGAG 1968delGGT 2145-56del 2355detATC Splice defects 1610A>G ivs2020+1G>A ivs2021-2A>G ivs2166+1G>A ivs2252-10G>A Frame shifts 442delC 488C>AT 524insT 660del34 663delC 684delG 787TGCTG>AGCATT 927delTA 977insT 1004del13 1079delGG 1171del7 1182delG 1521insC N 1 3 1 2 1 1 6 1 N 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 N 3 1 N 1 1 1 1 1 N 1 1 1 1 1 1 1 1 1 1 2 1 1 1 ALDP _ nd nd - - + - nd ALDP - - - - - nd nd nd nd nd nd nd nd nd - - ALDP nd nd nd - - nd nd nd ALDP nd nd - nd nd ALDP - nd nd nd nd nd nd - nd nd - nd nd - Reference 32 23,32,37 37 31,33 13 13 31,32,35,36,73 40 Reference 36 32 32 32 32 29 37 22 22 23 31 24,37 27 73 13 * Reference * 37 37 13,37,73 36 29 73 32 Reference 31 23 30 36 30 Reference 32 73 36 29 32 * 34 36 73 37 31,36 32 37 36 Total 1 1 1 1 1 1 1 1 Total 1 1 Total 1 1 1 1 1 1 1 1 Total 1 1 1 1 1 Total 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 al. Table I. Continued. Exon 4 5 5 5 6 6 6 8 8 9 start 1 2 2 3 3 3 6 7 7 7 8 8 9 Exon 6 10 Allele Fs A417 Fs V470 Fs V470 Fs E471 Fs F517 Fs G529 Fs P534 Fs A597 Fs S606 Fs D649 Allele 0.5 kb in exon 1 exon2del exon2-7del exon3-5del exon3-10del exon3-10del exon6-10del exon7-9del exon7-10del exon7-10del exon8-9del exon8-10del multiple exons Allele L516L Mutation 1250delC 1411insA 1412delAA 1415delAG 1551delC 1585delG alt1603-1991 1791delTA 1818delG 1949delGC 7 kb deletion Nucl.
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ABCD3 p.Gln590* 10227685:103:2625
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