ABCD1 p.Ser108Trp
| Predicted by SNAP2: | A: D (91%), C: D (91%), D: D (95%), E: D (95%), F: D (95%), G: D (91%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (91%), P: D (95%), Q: D (95%), R: D (95%), T: D (80%), V: D (95%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, T: N, V: D, W: D, Y: D, |
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[hide] Mutational and protein analysis of patients and he... Am J Hum Genet. 1996 Jun;58(6):1135-44. Feigenbaum V, Lombard-Platet G, Guidoux S, Sarde CO, Mandel JL, Aubourg P
Mutational and protein analysis of patients and heterozygous women with X-linked adrenoleukodystrophy.
Am J Hum Genet. 1996 Jun;58(6):1135-44., [PMID:8651290]
Abstract [show]
X-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder associated with impaired beta-oxidation of very-long-chain fatty acids (VLCFA), is due to mutations in a gene encoding a peroxisomal ATP-binding cassette (ABC) transporter (ALD protein [ALDP]). We analyzed the open reading frame of the ALD gene in 44 French ALD kindred by using SSCP or denaturing gradient-gel electrophoresis and studied the effect of mutations on ALDP by immunocytofluorescence and western blotting of fibroblasts and/or white blood cells. Mutations were detected in 37 of 44 kindreds and were distributed over the whole protein-coding region, with the exception of the C terminus encoded in exon 10. Except for two mutations (delAG1801 and P560L) observed four times each, nearly every ALD family has a different mutation. Twenty-four of 37 mutations were missense mutations leading to amino acid changes located in or close to putative transmembrane segments (TMS 2, 3, 4, and 5), in the EAA-like motif and in the nucleotide fold of the ATP-binding domain of ALDP. Of 38 ALD patients tested, 27 (71%) lacked ALDP immunoreactivity in their fibroblasts and/or white blood cells. More than half of missense mutations studied (11 of 21) resulted in a complete lack of ALDP immunoreactivity, and six missense mutations resulted in decreased ALDP expression. The fibroblasts and/or white blood cells of 15 of 15 heterozygous carrier from ALD kindred with no ALDP showed a mixture of positive- and negative-ALDP immunoreactivity due to X-inactivation. Since 5%-15% of heterozygous women have normal VLCFA levels, the immunodetection of ALDP in white blood cells can be applicable in a majority of ALD kindred, to identify heterozygous women, particularly when the ALD gene mutation has not yet been identified.
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No. Sentence Comment
76 58:1135-1144, 1996 Table 2 Mutations in the ALD Gene in Studied Patients AMINO ACID MUTATIONSb HOMOLOGUE INd KINDRED CLINICAL LOCALIZATION AMINO ACID ALDP BY NUMBER PHENOTYPEa DNA CpG Exon IN PROTEINC ALTERATION h/m ALDRP hPMP70 IF/WB' CALD, AMN CALD CALD CALD, AS AD CALD, AMN CALC AD AD AD ALMD CALD CALD, AMN CALD CALD, AMN, AD AMN ALMD CALD ALMD CALD AMN ALD AD, AMN, AS CALD, AS CALD CALD AD CALD AMN, ALMD CALD CALD AMN, ALMD CALD CALD, AMN, ALMD CALD CALD, ALMD, AS ALMD CALD AMN CALD, AMN AD AD AMN CALD G416A Ins T524 C679T C679T C700T C709G G732A A829G C840T Del TA927-28 A928G A985T A1048G DeIGC1080-81 C1174T G1266A ins C1521 1636delC DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 ins TGG 1848 G 1920 A C1938T C1938T G1950A C2065T C2065T C2065T C2065T C2065G G 2166+1 A T2202C DelGC 2335 C2364T C2364T No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found 1 1 + 1 + 1 1 1 + 1 1 + 1 1 1 1 1 1 1 + 1 3 4 S 5 S S S 6 + 6 + 6 6 + 7 + 7 + 7 + 7 + 7 + 7 8 9 9 9 W10 X Frameshift at L46 TMS2 S98L TMS2 S98L T1OSI S108W G116R TMS3 N148S TMS3 R152C Frameshift at Y180 Y181C TMS4 D200V TMS4 D221G Frameshift at R231 P263L EAA-like A294T Frameshift at V378 Frameshift at T416 Frameshift at E471 Frameshift at E471 Frameshift at E471 Frameshift at E471 ins val 491 Walker A G512S Walker A R518W Walker A R518W G 522 W P560L P560L P560L P560L P56OR Splice at G593 Walker B S606P Frameshift at D649 R660W R660W Absent Not done S A Present S A Present T T Absent S D Decreased G T Absent N N Present R K Present Absent Y Y Not done D D Not done D D Absent Absent P R Decreased A A Not done Absent Absent Absent Absent Absent Absent Absent G G Absent R R Absent R R Decreased G E Absent P P Decreased P P Decreased P P Decreased P P Absent P P Absent Not done S S Absent Absent R R Absent R R Absent Not done Absent Absent Absent Present Absent Absent a CALD = cerebral ALD (5-15 years); AMN = adrenomyeloneuropathy; ALMD = adrenomyeloneuropathy with cerebral involvement; AD = Addison disease; AS = Asymptomatic.
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ABCD1 p.Ser108Trp 8651290:76:1100
status: NEW131 Lane 1, protein markers; lane 2, control; lane 3, patient 18 (S108W); lane 4, patient 32 (P263L); lane 5, patient 5 (P560L); lane 6, patient 4 (G116R); lane 7, patient 19 (D221G); lane 8, patient 33 (S98L); lane 9, patient 78 (S606P); lane 10, patient 3 (no mutation found); lane 11, patient 37 (P560L); lane 12, patient 22 (R660W); lane 13, control; lane 14, patient 39 (T1051); lane 15, patient 4 (G116R); lane 16, patient 43 (frameshift at Y180); lane 17, patient 5 (P560L); lane 18, patient 59 (G512S); lane 19, patient 29 (frameshift at D649); lane 20, patient 69 (P560L); lane 21, patient 19 (D221G); lane 22, patient 64 (W1OX); lane 23, patient 63 (frameshift at R231); lane 24, patient 52 (no mutation found); lane 25, patient 61 (frameshift at E471); and lane 26, patient 83 (G522W).
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ABCD1 p.Ser108Trp 8651290:131:62
status: NEW173 Four missense mutations (S108W, P263L, R518W, and P560L) resulted in decreased ALDP immunoreactivity reflecting likely instability and/or partial deficiency in the peroxisomal targeting of ALDP.
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ABCD1 p.Ser108Trp 8651290:173:25
status: NEW174 Three missense mutations (S98L, N148S, and R152C) resulted in the synthesis of a stable but presumably nonfunctioning protein.
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ABCD1 p.Ser108Trp 8651290:174:25
status: NEW75 58:1135-1144, 1996 Table 2 Mutations in the ALD Gene in Studied Patients AMINO ACID MUTATIONSb HOMOLOGUE INd KINDRED CLINICAL LOCALIZATION AMINO ACID ALDP BY NUMBER PHENOTYPEa DNA CpG Exon IN PROTEINC ALTERATION h/m ALDRP hPMP70 IF/WB' CALD, AMN CALD CALD CALD, AS AD CALD, AMN CALC AD AD AD ALMD CALD CALD, AMN CALD CALD, AMN, AD AMN ALMD CALD ALMD CALD AMN ALD AD, AMN, AS CALD, AS CALD CALD AD CALD AMN, ALMD CALD CALD AMN, ALMD CALD CALD, AMN, ALMD CALD CALD, ALMD, AS ALMD CALD AMN CALD, AMN AD AD AMN CALD G416A Ins T524 C679T C679T C700T C709G G732A A829G C840T Del TA927-28 A928G A985T A1048G DeIGC1080-81 C1174T G1266A ins C1521 1636delC DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 ins TGG 1848 G 1920 A C1938T C1938T G1950A C2065T C2065T C2065T C2065T C2065G G 2166+1 A T2202C DelGC 2335 C2364T C2364T No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found 1 1 + 1 + 1 1 1 + 1 1 + 1 1 1 1 1 1 1 + 1 3 4 S 5 S S S 6 + 6 + 6 6 + 7 + 7 + 7 + 7 + 7 + 7 8 9 9 9 W10 X Frameshift at L46 TMS2 S98L TMS2 S98L T1OSI S108W G116R TMS3 N148S TMS3 R152C Frameshift at Y180 Y181C TMS4 D200V TMS4 D221G Frameshift at R231 P263L EAA-like A294T Frameshift at V378 Frameshift at T416 Frameshift at E471 Frameshift at E471 Frameshift at E471 Frameshift at E471 ins val 491 Walker A G512S Walker A R518W Walker A R518W G 522 W P560L P560L P560L P560L P56OR Splice at G593 Walker B S606P Frameshift at D649 R660W R660W Absent Not done S A Present S A Present T T Absent S D Decreased G T Absent N N Present R K Present Absent Y Y Not done D D Not done D D Absent Absent P R Decreased A A Not done Absent Absent Absent Absent Absent Absent Absent G G Absent R R Absent R R Decreased G E Absent P P Decreased P P Decreased P P Decreased P P Absent P P Absent Not done S S Absent Absent R R Absent R R Absent Not done Absent Absent Absent Present Absent Absent a CALD = cerebral ALD (5-15 years); AMN = adrenomyeloneuropathy; ALMD = adrenomyeloneuropathy with cerebral involvement; AD = Addison disease; AS = Asymptomatic.
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ABCD1 p.Ser108Trp 8651290:75:1100
status: NEW[hide] Simultaneous quantitative and allele-specific expr... BMC Genet. 2004 May 5;5:8. Ding C, Maier E, Roscher AA, Braun A, Cantor CR
Simultaneous quantitative and allele-specific expression analysis with real competitive PCR.
BMC Genet. 2004 May 5;5:8., [PMID:15128429]
Abstract [show]
BACKGROUND: For a diploid organism such as human, the two alleles of a particular gene can be expressed at different levels due to X chromosome inactivation, gene imprinting, different local promoter activity, or mRNA stability. Recently, imbalanced allelic expression was found to be common in human and can follow Mendelian inheritance. Here we present a method that employs real competitive PCR for allele-specific expression analysis. RESULTS: A transcribed mutation such as a single nucleotide polymorphism (SNP) is used as the marker for allele-specific expression analysis. A synthetic mutation created in the competitor is close to a natural mutation site in the cDNA sequence. PCR is used to amplify the two cDNA sequences from the two alleles and the competitor. A base extension reaction with a mixture of ddNTPs/dNTP is used to generate three oligonucleotides for the two cDNAs and the competitor. The three products are identified and their ratios are calculated based on their peak areas in the MALDI-TOF mass spectrum. Several examples are given to illustrate how allele-specific gene expression can be applied in different biological studies. CONCLUSIONS: This technique can quantify the absolute expression level of each individual allele of a gene with high precision and throughput.
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No. Sentence Comment
132 The ddNTPs/dNTP mixtures are: ddATP/ddCTP/ddGTP/dTTP for interleukin 6 and ABCD1 Q672X, ddTTP/ddCTP/ddGTP/dATP for lexA, and ddATP/ddCTP/ddTTP/dGTP for ABCD-1 S108W and S213C.
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ABCD1 p.Ser108Trp 15128429:132:159
status: NEW[hide] Molecular characterization of 21 X-ALD Portuguese ... Mol Genet Metab. 2002 May;76(1):62-7. Guimaraes CP, Lemos M, Sa-Miranda C, Azevedo JE
Molecular characterization of 21 X-ALD Portuguese families: identification of eight novel mutations in the ABCD1 gene.
Mol Genet Metab. 2002 May;76(1):62-7., [PMID:12175782]
Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder. The gene associated with X-ALD, ABCD1, encodes a peroxisomal ATP-binding cassette half-transporter. In this study, we describe the molecular characterization of 21 affected Portuguese families. The complete coding region of the ABCD1 gene was amplified by reverse transcription polymerase chain reaction (RT-PCR) or genomic PCR. After conformation-sensitive gel electrophoresis analysis, fragments with a conformational heteroduplex pattern were sequenced. Using this strategy, we have identified 14 missense mutations, two nonsense mutations, two splicing site defects, and three small deletions, two of them resulting in frameshifts. Eight of the genetic alterations characterized in this study are novel. The levels of the ABCD1 transcript as well as the levels of ALDP in cultured skin fibroblasts of male probands were also determined in most cases. The levels of the ABCD1 transcript in one patient (corresponding to a nonsense mutation) were below the detection limit of Northern-blotting analysis. ALDP was found at normal levels in only three patients, absent in five (corresponding to a double missense, two nonsense, and two frameshift mutations), and decreased in all the others.
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66 Type of genetic alteration Exon RT-PCR fragmenta Nucleotide change Amplicon usedb /RFLP associatedc ALDP (WB) ABCD1 mRNA (NB) References Missense 1 S103R 1 F2 c.309C > G ALDe1A/þCfoI Diminished Detectable [19] 2 S108W 1 - c.323C > G ALDe1B/þRleAI Not done Not done [18] 3 S108L 1 - c.323C > T - Normal Not done [20] 4 L114P 1 F2 c.341T > C ALDe1B/ÀEcoRII Diminished Detectable Novel mutation 5 ½R236H; G512S 1 F3 [c.707G > A; ALDe1C/þNcoI Novel mutation 6 F6 c.1534G > A] ALDe6/þPstI Not detectable Not done [16,17] 6 G266R 1 F3 c.796G > A - Normal Detectable [21] 7 R518W 6 F6 c.1552C > T ALDe6/ÀHpaII Diminished Detectable [22] 8 R518Q 6 F6 c.1153G > A ALDe6/ÀBamHI Diminished Not done [23] 9 R545W 6 - c.1633A > T ALDe6/þTspRI Not done Not done Novel mutation 10 R591W 7 F7 c.1171C > T ALDe7/ÀAciI Normal Not done [24] 11 L655P 9 F8 c.1964T > C ALDe8/9/ÀSapId Diminished Detectable Novel mutation 12 R660W 9 F7/F8 c.1978C > T ALDe8/9/þBsrI Diminished Detectable [16,17,25] 13 H667L 10 F8 c.2000A > T ALDe10/þDdeId Diminished Detectable Novel mutation Nonsense 14 Q574X 7 F6 c.1720C > T ALDe7/ÀAlwNI Not detectable Detectable Novel mutation 15 W601X 8 F7 c.1802G > A ALDe8/9/ÀBsrI Not detectable Not detectable [9] Frameshift 16 fs G298 1 F3 [c.893delG; c.894C > T] ALDe1C/ÀNlaIV Not detectable Detectable Novel mutation 17, 18 fs E472 5 F5 c.1415-1416delAG - Not detectable Detectable [21,26,27] Microdeletion 19 F175del 1 F2 c.522-524delCTT d Diminished Detectable Novel mutation Splicing defect 20 Splicing IVS1 - c.900G > A - Not done Not done [10] 21 Splicing IVS7 - c.1760+1G > A - Not done Not done [18] Polymorphism 1, 5 F673F 8 F8 c.2019C > T ÀTaqI - - [28] 1, 2, 5, 11, 13 30 UTR F8 - ÀDrdI - - [27] a RT-PCR fragment (defined according to [10]) which shows heteroduplex molecules in a CSGE analysis.
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ABCD1 p.Ser108Trp 12175782:66:216
status: NEW[hide] Two novel missense mutations causing adrenoleukody... Mol Cell Probes. 1999 Jun;13(3):179-82. Perusi C, Gomez-Lira M, Mottes M, Pignatti PF, Bertini E, Cappa M, Vigliani MC, Schiffer D, Rizzuto N, Salviati A
Two novel missense mutations causing adrenoleukodystrophy in Italian patients.
Mol Cell Probes. 1999 Jun;13(3):179-82., [PMID:10369742]
Abstract [show]
The authors present two new missense mutations in exon 1 of the adrenoleukodystrophy (ALD) gene. The first, a C813T transition, results in the substitution Pro143 Ser in the third putative transmembrane domain of the adrenoleukodystrophy protein (ALDP) in an adult onset case. The second, a de novo C709T transition, results in a substitution Ser 108 Leu between the second and the third putative transmembrane segments, in a childhood case.
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44 Other mutations in this segment have been described that cause ALD including the substitution of serine 108 for tryptophan described in a ChALD and in an AMN.9 The authors9 demonstrated that the substitution of this serine for tryptophan showed decreased ALDP immunoreactivity and a weak 75 kD ALDP band on Western blotting indicating that the substitution of serine 108 probably results in the synthesis of an unstable protein that is rapidly degraded in the cytosol.
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ABCD1 p.Ser108Trp 10369742:44:97
status: NEW45 Other mutations in this segment have been described that cause ALD including the substitution of serine 108 for tryptophan described in a ChALD and in an AMN.9 The authors9 demonstrated that the substitution of this serine for tryptophan showed decreased ALDP immunoreactivity and a weak 75 kD ALDP band on Western blotting indicating that the substitution of serine 108 probably results in the synthesis of an unstable protein that is rapidly degraded in the cytosol.
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ABCD1 p.Ser108Trp 10369742:45:97
status: NEW