ABCD1 p.Glu609Lys
ClinVar: |
c.1825G>A
,
p.Glu609Lys
D
, Pathogenic
|
Predicted by SNAP2: | A: D (91%), C: D (95%), D: D (91%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%), |
Predicted by PROVEAN: | A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: N, R: D, S: D, T: D, V: D, W: D, Y: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
174 P560S 7 1678C>T n.d. # P560L 7 1679C>T Reduced P560L 7 1679C>T Reduced fs I588 7 1765delC n.d. # R591P 7 1772G>C Absent S606L 8 1817C>T Present E609K 8 1825G>A Absent E609K 8 1825G>A Absent R617C 8 1849C>T Absent R617H 8 1850G>A Absent R617H 8 1850G>A Absent A626T 9 1876G>A Absent A626T 9 1876G>A Absent A626D 9 1877C>A n.d. # E630G 9 1889A>G n.d. # C631Y 9 1892G>A n.d. # T632I 9 1895C>T n.d. # V635M 9 1903G>A n.d. # L654P 9 1961T>C Absent # R660W 9 1978C>T Absent fs L663 9 1988insT n.d. # fs L663 IVS 9 IVS9+1g>a n.d. # fs L663 IVS 9 IVS9-1g>a n.d. # H667D 10 1999C>G Absent # T668I 10 2003C>T Absent # T693M 10 2078C>T Present # exon1-5del 1-5 n.d. # The 47 mutations marked with a # are novel unique mutations reported for the first time in this paper.
X
ABCD1 p.Glu609Lys 11748843:174:144
status: NEWX
ABCD1 p.Glu609Lys 11748843:174:167
status: NEW[hide] Identification of novel SNPs of ABCD1, ABCD2, ABCD... Neurogenetics. 2011 Feb;12(1):41-50. Epub 2010 Jul 27. Matsukawa T, Asheuer M, Takahashi Y, Goto J, Suzuki Y, Shimozawa N, Takano H, Onodera O, Nishizawa M, Aubourg P, Tsuji S
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.
Neurogenetics. 2011 Feb;12(1):41-50. Epub 2010 Jul 27., [PMID:20661612]
Abstract [show]
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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
84 Interestingly, the five previously described SNPs (rs17782508, rs2301345, rs4148077, rs4148078, and rs3742801) that are in complete linkage disequilibrium were significantly less frequently represented in the patients with Japanese AMN than in the controls in the Japanese population (p=0.0468), whereas Table 2 Identified ABCD1 mutations: mutations of ABCD1 that result in amino acid substitutions or in-frame deletions Patient number Phenotype Mutation of ABCD1 Effect of mutation of ABCD1 Position of mutation 13 CCALD 709C>T S108L Loop1 14 CCALD 709C>T S108L Loop1 15 CCALD 829A>G N148S TM2 16 CCALD 1026A>G N214D TM3 17 CCALD 1182G>A G266R Between TM4 and EAA-like 18 CCALD 1324T>Ca L313P Between EAA-like and TM5 19 CCALD 1938C>T R518W Walker A 20 CCALD 1939G>A R518Q Walker A 21 CCALD 2017A>G Q544R Between Walker A and Cons 22 CCALD 2017A>G Q544R Between Walker A and Cons 23 CCALD 2065C>T P560L Between Walker A and Cons 24 CCALD 2065C>T P560L Between Walker A and Cons 25 CCALD Del. 2145-2156 Del. HILQ587-590 Between Walker A and Cons 26 AdultCer Del. 1257-1259 Del.E291 EAA-like 27 AdultCer 2005T>C F540S Between Walker A and Cons 28 AdultCer 2358C>T R660W C-terminal to Walker B 29 AdultCer 2385C>A H667N C-terminal to Walker B 30 AMN-Cer 1146A>C T254P TM4 31 AMN 636C>T P84S TM1 32 AMN 709C>T S108L Loop1 33 AMN 1182G>A G266R Between TM4 and EAA-like 34 AMN 1197G>A E271K Between TM4 and EAA-like 35 AMN 1215G>Aa G277R Between TM4 and EAA-like 36 AMN 1255C>G S290W EAA-like 37 AMN 1581C>T R401W Between TM6 and Walker A 38 AMN 2233C>A A616D Cons 39 AMN 2385C>A H667N C-terminal to Walker B 40 Asymptomatic 2211G>A E609K Cons Amino acid residue numbers in ALDP are based on Mosser et al. [1].
X
ABCD1 p.Glu609Lys 20661612:84:1628
status: NEW[hide] Conservation of targeting but divergence in functi... Biochem J. 2011 Jun 15;436(3):547-57. Zhang X, De Marcos Lousa C, Schutte-Lensink N, Ofman R, Wanders RJ, Baldwin SA, Baker A, Kemp S, Theodoulou FL
Conservation of targeting but divergence in function and quality control of peroxisomal ABC transporters: an analysis using cross-kingdom expression.
Biochem J. 2011 Jun 15;436(3):547-57., [PMID:21476988]
Abstract [show]
ABC (ATP-binding cassette) subfamily D transporters are found in all eukaryotic kingdoms and are known to play essential roles in mammals and plants; however, their number, organization and physiological contexts differ. Via cross-kingdom expression experiments, we have explored the conservation of targeting, protein stability and function between mammalian and plant ABCD transporters. When expressed in tobacco epidermal cells, the mammalian ABCD proteins ALDP (adrenoleukodystrophy protein), ALDR (adrenoleukodystrophy-related protein) and PMP70 (70 kDa peroxisomal membrane protein) targeted faithfully to peroxisomes and P70R (PMP70-related protein) targeted to the ER (endoplasmic reticulum), as in the native host. The Arabidopsis thaliana peroxin AtPex19_1 interacted with human peroxisomal ABC transporters both in vivo and in vitro, providing an explanation for the fidelity of targeting. The fate of X-linked adrenoleukodystrophy disease-related mutants differed between fibroblasts and plant cells. In fibroblasts, levels of ALDP in some 'protein-absent' mutants were increased by low-temperature culture, in some cases restoring function. In contrast, all mutant ALDP proteins examined were stable and correctly targeted in plant cells, regardless of their fate in fibroblasts. ALDR complemented the seed germination defect of the Arabidopsis cts-1 mutant which lacks the peroxisomal ABCD transporter CTS (Comatose), but neither ALDR nor ALDP was able to rescue the defect in fatty acid beta-oxidation in establishing seedlings. Taken together, our results indicate that the mechanism for trafficking of peroxisomal membrane proteins is shared between plants and mammals, but suggest differences in the sensing and turnover of mutant ABC transporter proteins and differences in substrate specificity and/or function.
Comments [show]
None has been submitted yet.
No. Sentence Comment
153 Approximately 60% of X-ALD ABCD1 mutations are missense mutations, 65% of which result in no detectable ALDP, based on IF (immunofluorescence), indicating that they affect protein Table 1 Quantification of ALDP levels in X-ALD fibroblasts ALDP Mutation IF Immunoblot (% of control) p.Arg74Trp Absent 7.5 + - 0.6 p.Arg104Cys Reduced 35 + - 3.0 p.Ser149Asn Present 77 + - 3.0 p.Asp194His Present 60 + - 13.6 p.Leu220Pro Reduced 21.8 + - 5.4 p.Arg389His Present 40.6 + - 3.6 p.Arg554His Absent 1.0 + - 0.5 p.Ser606Leu Present 25 + - 1.5 p.Glu609Gly Absent 2.1 + - 1.3 p.Glu609Lys Absent 1.8 + - 0.9 p.Ala616Thr Absent 4.3 + - 1.7 p.Leu654Pro Absent 1.5 + - 1.3 p.Arg660Trp Absent 1.6 + - 0.8 p.His667Asp Absent 2.9 + - 1.0 p.Arg113fs Absent - Figure 3 Interaction of mammalian ABCD proteins with Arabidopsis Pex19 in vivo Tobacco plants stably expressing CFP-SKL were co-transfected with 35S::ABCD-YFP fusions andNLS-Pex19constructs.Leafepidermalcellswereimagedusingconfocalmicroscopy:(A-D) ALDP-YFP plus NLS-HsPex19; (E-H) ALDP-YFP plus NLS-AtPex19_1; (I-L) ALDR-YFP plus NLS-AtPex19_1.
X
ABCD1 p.Glu609Lys 21476988:153:567
status: NEW172 ALDP was increased from 2-4% to ~20% of wild-type levels in cell lines bearing the mutations p.Glu609Gly, p.Ala616Thr and p.Arg660Trp, from 1 to 10% in p.Glu609Lys and p.Arg554His cells and from 45 to 75% in the p.Asp194His cell line (Figure 4A).
X
ABCD1 p.Glu609Lys 21476988:172:154
status: NEW173 VLCFA β-oxidation was measured in cells that were cultured at 30◦ C for 72 h, but in only one case (p.Ala616Thr) was the capacity to degrade VLCFA restored to near-control levels (Figure 4C).
X
ABCD1 p.Glu609Lys 21476988:173:154
status: NEW154 Approximately 60% of X-ALD ABCD1 mutations are missense mutations, 65% of which result in no detectable ALDP, based on IF (immunofluorescence), indicating that they affect protein Table 1 Quantification of ALDP levels in X-ALD fibroblasts ALDP Mutation IF Immunoblot (% of control) p.Arg74Trp Absent 7.5 + - 0.6 p.Arg104Cys Reduced 35 + - 3.0 p.Ser149Asn Present 77 + - 3.0 p.Asp194His Present 60 + - 13.6 p.Leu220Pro Reduced 21.8 + - 5.4 p.Arg389His Present 40.6 + - 3.6 p.Arg554His Absent 1.0 + - 0.5 p.Ser606Leu Present 25 + - 1.5 p.Glu609Gly Absent 2.1 + - 1.3 p.Glu609Lys Absent 1.8 + - 0.9 p.Ala616Thr Absent 4.3 + - 1.7 p.Leu654Pro Absent 1.5 + - 1.3 p.Arg660Trp Absent 1.6 + - 0.8 p.His667Asp Absent 2.9 + - 1.0 p.Arg113fs Absent - Figure 3 Interaction of mammalian ABCD proteins with Arabidopsis Pex19 in vivo Tobacco plants stably expressing CFP-SKL were co-transfected with 35S::ABCD-YFP fusions andNLS-Pex19constructs.Leafepidermalcellswereimagedusingconfocalmicroscopy:(A-D) ALDP-YFP plus NLS-HsPex19; (E-H) ALDP-YFP plus NLS-AtPex19_1; (I-L) ALDR-YFP plus NLS-AtPex19_1.
X
ABCD1 p.Glu609Lys 21476988:154:567
status: NEW[hide] Hematopoietic stem cell gene therapy with a lentiv... Science. 2009 Nov 6;326(5954):818-23. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrere F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougneres P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P
Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.
Science. 2009 Nov 6;326(5954):818-23., [PMID:19892975]
Abstract [show]
X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors. Autologous CD34+ cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1, and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, we detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.
Comments [show]
None has been submitted yet.
No. Sentence Comment
30 These two patients, aged 7.5 years (P1) and 7 years (P2), had ABCD1 gene mutations (a large deletion from exon 6 in P1 and E609K mutation in P2), resulting in the absence of ALD protein detectable by immunocytochemistry in fibroblasts and white blood cells.
X
ABCD1 p.Glu609Lys 19892975:30:123
status: NEW26 These two patients, aged 7.5 years (P1) and 7 years (P2), had ABCD1 gene mutations (a large deletion from exon 6 in P1 and E609K mutation in P2), resulting in the absence of ALD protein detectable by immunocytochemistry in fibroblasts and white blood cells.
X
ABCD1 p.Glu609Lys 19892975:26:123
status: NEW[hide] Genomic profiling identifies novel mutations and S... PLoS One. 2011;6(9):e25094. Epub 2011 Sep 22. Kumar N, Taneja KK, Kalra V, Behari M, Aneja S, Bansal SK
Genomic profiling identifies novel mutations and SNPs in ABCD1 gene: a molecular, biochemical and clinical analysis of X-ALD cases in India.
PLoS One. 2011;6(9):e25094. Epub 2011 Sep 22., [PMID:21966424]
Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and adrenal cortex secondary to mutations in the ABCD1 gene that encode the peroxisomal membrane protein. We conducted a genomic and protein expression study of susceptibility gene with its clinical and biochemical analysis. To the best of our knowledge this is the first preliminary comprehensive study in Indian population that identified novel mutations and SNPs in a relatively large group. We screened 17 Indian indigenous X-linked adrenoleukodystrophy cases and 70 controls for mutations and SNPs in the exonic regions (including flanking regions) of ABCD1 gene by direct sequencing with ABI automated sequencer along with Western blot analysis of its endogenous protein, ALDP, levels in peripheral blood mononuclear cells. Single germ line mutation was identified in each index case in ABCD1 gene. We detected 4 novel mutations (2 missense and 2 deletion/insertion) and 3 novel single nucleotide polymorphisms. We observed a variable protein expression in different patients. These findings were further extended to biochemical and clinical observations as it occurs with great clinical expression variability. This is the first major study in this population that presents a different molecular genetic spectrum as compared to Caucasian population due to geographical distributions of ethnicity of patients. It enhances our knowledge of the causative mutations of X-ALD that grants holistic base to develop effective medicine against X-ALD.
Comments [show]
None has been submitted yet.
No. Sentence Comment
103 Of the 10 non-recurrent mutations in our study group i.e a frameshift mutation c.110_117del8 (Val36fs) in exon 1 was identified in an asymptomatic heterozygous female and 5 missense mutations, c.904G.A (Glu302Lys) in exon 2, c.1202G.A (Arg401Gln) in exon 3, c.1771C.T (Arg591Trp) in exon 7, c.1816T.C (Ser606Pro) and c.1825G.A (Glu609Lys) in exon 8 were present in 5 different patients.
X
ABCD1 p.Glu609Lys 21966424:103:328
status: NEW156 Patients Phenotype1 Age(Year) Sex Exon/IVS Mutation Type Mutations Protein Localization ALDP PSIC Score5 P01* ccALD 4 M 9 Inframe del/ins c.1903_04delinsCCA/Val635delinsAlaMet NBF + + - P02* ccALD 5 M 9 Missense c.1979G.A/Arg660Gln - - 2.409 P03 ccALD 3 M IVS84 Frameshift g.1866-10G.A/Arg622fs Walker B3 - - P04 ccALD 4.5 M 1 Missense c.796G.A/Gly266Arg TMD + ++ 2.539 P05 ccALD 6 M 9 Frameshift c.1939_40insGG/Ala646fs NBF n.d - P06 ccALD 7 M 2 Missense c.904G.A/Glu302Lys TMD + + 2.194 P07 ccALD 8 M 3 Missense c.1202G.A/Arg401Gln - + ++ 2.396 P08* ccALD 8 M 10 Inframe del/ins c.1993_95delinsGAG/Lys665delinsGlu - + + - P09 AdolCALD 11 M 1 Missense c.796G.A/Gly266Arg TMD + ++ 2.539 P10 AdolCALD 11 M 8 Missense c.1816T.C/Ser606Pro C sequence - 2.499 P11 AdolCALD 15 M IVS8 Frameshift g.1866-10G.A/Arg622fs Walker B + - P12 ACALD 42 M 8 Missense c.1825G.A/Glu609Lys C sequence3 - 2.075 P13* ACALD 46 M 7 Missense c.1673T.C/Ile558Thr NBF3 + ++ 1.211 P14 AMN 26 M 9 Frameshift c.1939_40insGG/Ala646fs - - - P15 AMN 35 M 1 Missense c.796G.A/Gly266Arg TMD2 + ++ 2.539 P16 Asymptomatic 18 F 7 Missense c.1771C.T/Arg591Trp NBF + ++ 2.818 P17 Asymptomatic 26 F 1 Frameshift c.110_17del8/Val36fs - + + - *Novel Mutations, 1 ccALD-Childhood Adrenoleukodystrophy, AMN-Adrenomyeloneuropathy, ACALD-Adult Cerebral Adrenoleukodystrophy, AdolCALD- Adolescent cerebral Adrenoleukodystrophy.
X
ABCD1 p.Glu609Lys 21966424:156:860
status: NEW168 Lane 1 and 10 (Control by symbol ''C``), Lane 2 (P01, ccALD, V635delins A & M), Lane 3 (P02, ccALD, R660Q), Lane 4 (P03, ccALD, R622fs), Lane 5 (P04, ccALD, G266R), Lane 6 (P06, ccALD, E302K), Lane 7 (P07, ccALD, R401Q), Lane 8 (P08, ccALD, K665delinsE), Lane 9 (P09, AdolCALD, G266R), Lane 11 (P10, AdolCALD, S606P), Lane 12 (P11, AdolCALD, R622fs), Lane 13 (P12, ACALD, E609K), Lane 14 (P13, ACALD, I558T), Lane 15 (P14, AMN, A646fs), Lane 16 (P15, AMN, G266R), Lane 17 (P16, asymptomatic female, R591W) and Lane 18 (P17, asymptomatic female,).
X
ABCD1 p.Glu609Lys 21966424:168:372
status: NEW198 Supporting Information Supporting Information S1 Frequently occurring mutations in (a) intervening sequence 8 (g.1866-10G.A/Arg622fs, shown as C.T in antisense strand) in P03 and P11, (b) exon 1 (c.796G.A/ Gly266Arg, shown as C.T in antisense strand) in P04, P09 and P15, (c) exon 9 (c.1939_40insGG/Ala646fs, shown as CC in antisense strand) in P05 and P14, (d) exon 2 (c.904G.A/ Glu302Lys) in P06, (e) exon 3 (c.1202G.A/Arg401Gln) in P07, (f) exon 8 (c.1816T.C/Ser606Pro) in P10, (g) exon 8 (c.1825G.A/ Glu609Lys) in P12, (h) exon 7 (c.1771C.T/Arg591Trp) in P16 and (i) exon 1 (c.110_17del8/Val36fs) in P17.
X
ABCD1 p.Glu609Lys 21966424:198:504
status: NEW102 Of the 10 non-recurrent mutations in our study group i.e a frameshift mutation c.110_117del8 (Val36fs) in exon 1 was identified in an asymptomatic heterozygous female and 5 missense mutations, c.904G.A (Glu302Lys) in exon 2, c.1202G.A (Arg401Gln) in exon 3, c.1771C.T (Arg591Trp) in exon 7, c.1816T.C (Ser606Pro) and c.1825G.A (Glu609Lys) in exon 8 were present in 5 different patients.
X
ABCD1 p.Glu609Lys 21966424:102:328
status: NEW155 Patients Phenotype1 Age(Year) Sex Exon/IVS Mutation Type Mutations Protein Localization ALDP PSIC Score5 P01* ccALD 4 M 9 Inframe del/ins c.1903_04delinsCCA/Val635delinsAlaMet NBF + + - P02* ccALD 5 M 9 Missense c.1979G.A/Arg660Gln - - 2.409 P03 ccALD 3 M IVS84 Frameshift g.1866-10G.A/Arg622fs Walker B3 - - P04 ccALD 4.5 M 1 Missense c.796G.A/Gly266Arg TMD + ++ 2.539 P05 ccALD 6 M 9 Frameshift c.1939_40insGG/Ala646fs NBF n.d - P06 ccALD 7 M 2 Missense c.904G.A/Glu302Lys TMD + + 2.194 P07 ccALD 8 M 3 Missense c.1202G.A/Arg401Gln - + ++ 2.396 P08* ccALD 8 M 10 Inframe del/ins c.1993_95delinsGAG/Lys665delinsGlu - + + - P09 AdolCALD 11 M 1 Missense c.796G.A/Gly266Arg TMD + ++ 2.539 P10 AdolCALD 11 M 8 Missense c.1816T.C/Ser606Pro C sequence - 2.499 P11 AdolCALD 15 M IVS8 Frameshift g.1866-10G.A/Arg622fs Walker B + - P12 ACALD 42 M 8 Missense c.1825G.A/Glu609Lys C sequence3 - 2.075 P13* ACALD 46 M 7 Missense c.1673T.C/Ile558Thr NBF3 + ++ 1.211 P14 AMN 26 M 9 Frameshift c.1939_40insGG/Ala646fs - - - P15 AMN 35 M 1 Missense c.796G.A/Gly266Arg TMD2 + ++ 2.539 P16 Asymptomatic 18 F 7 Missense c.1771C.T/Arg591Trp NBF + ++ 2.818 P17 Asymptomatic 26 F 1 Frameshift c.110_17del8/Val36fs - + + - *Novel Mutations, 1 ccALD-Childhood Adrenoleukodystrophy, AMN-Adrenomyeloneuropathy, ACALD-Adult Cerebral Adrenoleukodystrophy, AdolCALD- Adolescent cerebral Adrenoleukodystrophy.
X
ABCD1 p.Glu609Lys 21966424:155:860
status: NEW167 Lane 1 and 10 (Control by symbol ''C``), Lane 2 (P01, ccALD, V635delins A & M), Lane 3 (P02, ccALD, R660Q), Lane 4 (P03, ccALD, R622fs), Lane 5 (P04, ccALD, G266R), Lane 6 (P06, ccALD, E302K), Lane 7 (P07, ccALD, R401Q), Lane 8 (P08, ccALD, K665delinsE), Lane 9 (P09, AdolCALD, G266R), Lane 11 (P10, AdolCALD, S606P), Lane 12 (P11, AdolCALD, R622fs), Lane 13 (P12, ACALD, E609K), Lane 14 (P13, ACALD, I558T), Lane 15 (P14, AMN, A646fs), Lane 16 (P15, AMN, G266R), Lane 17 (P16, asymptomatic female, R591W) and Lane 18 (P17, asymptomatic female,).
X
ABCD1 p.Glu609Lys 21966424:167:372
status: NEW197 Supporting Information Supporting Information S1 Frequently occurring mutations in (a) intervening sequence 8 (g.1866-10G.A/Arg622fs, shown as C.T in antisense strand) in P03 and P11, (b) exon 1 (c.796G.A/ Gly266Arg, shown as C.T in antisense strand) in P04, P09 and P15, (c) exon 9 (c.1939_40insGG/Ala646fs, shown as CC in antisense strand) in P05 and P14, (d) exon 2 (c.904G.A/ Glu302Lys) in P06, (e) exon 3 (c.1202G.A/Arg401Gln) in P07, (f) exon 8 (c.1816T.C/Ser606Pro) in P10, (g) exon 8 (c.1825G.A/ Glu609Lys) in P12, (h) exon 7 (c.1771C.T/Arg591Trp) in P16 and (i) exon 1 (c.110_17del8/Val36fs) in P17.
X
ABCD1 p.Glu609Lys 21966424:197:504
status: NEW[hide] Spectrum of mutations in the gene encoding the adr... Am J Hum Genet. 1995 Jan;56(1):44-50. Ligtenberg MJ, Kemp S, Sarde CO, van Geel BM, Kleijer WJ, Barth PG, Mandel JL, van Oost BA, Bolhuis PA
Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein.
Am J Hum Genet. 1995 Jan;56(1):44-50., [PMID:7825602]
Abstract [show]
X-linked adrenoleukodystrophy (ALD) has been associated with mutations in a gene encoding an ATP-binding transporter, which is located in the peroxisomal membrane. Deficiency of the gene leads to impaired peroxisomal beta-oxidation. Systematic analysis of the open reading frame of the ALD gene, using reverse transcriptase-PCR, followed by direct sequencing, revealed mutations in all 28 unrelated kindreds analyzed. No entire gene deletions or drastic promoter mutations were detected. In only one kindred did the mutation involve multiple exons. The other mutations were small alterations leading to missense (13 of 28) or nonsense mutations, a single amino acid deletion, frameshifts, or splice acceptor-site defects. Mutations affecting a single amino acid were concentrated in the region between the third and fourth putative transmembrane domains and in the ATP-binding domain. Mutations were detected in all investigated ALD kindreds, suggesting that this gene is the only gene responsible for X-linked ALD. This overview of mutations is useful in the determination of structurally and functionally important regions and provides an efficient screening strategy for identification of mutations in the ALD gene.
Comments [show]
None has been submitted yet.
No. Sentence Comment
150 Exceptions are one of the ATP-binding-site motif mutations (E609K), which was detected in 2 kindreds, and a dinucleotide deletion resulting in a frameshift immediately downstream of E471, which was observed in 4 of the above kindreds and 1 of 10 different kindreds screened for this mutation on genomic DNA only (Kemp et al. 1994b).
X
ABCD1 p.Glu609Lys 7825602:150:60
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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
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).
X
ABCD1 p.Glu609Lys 15800013:76:636
status: NEW[hide] X-linked adrenoleukodystrophy in women: a cross-se... Brain. 2014 Mar;137(Pt 3):693-706. doi: 10.1093/brain/awt361. Epub 2014 Jan 29. Engelen M, Barbier M, Dijkstra IM, Schur R, de Bie RM, Verhamme C, Dijkgraaf MG, Aubourg PA, Wanders RJ, van Geel BM, de Visser M, Poll-The BT, Kemp S
X-linked adrenoleukodystrophy in women: a cross-sectional cohort study.
Brain. 2014 Mar;137(Pt 3):693-706. doi: 10.1093/brain/awt361. Epub 2014 Jan 29., [PMID:24480483]
Abstract [show]
X-linked adrenoleukodystrophy is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal transporter of very long-chain fatty acids. A defect in the ABCD1 protein results in elevated levels of very long-chain fatty acids in plasma and tissues. The clinical spectrum in males with X-linked adrenoleukodystrophy has been well described and ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. As in many X-linked diseases, it was assumed that female carriers remain asymptomatic and only a few studies addressed the phenotype of X-linked adrenoleukodystrophy carriers. These studies, however, provided no information on the prevalence of neurological symptoms in the entire population of X-linked adrenoleukodystrophy carriers, since data were acquired in small groups and may be biased towards women with symptoms. Our primary goal was to investigate the symptoms and their frequency in X-linked adrenoleukodystrophy carriers. The secondary goal was to determine if the X-inactivation pattern of the ABCD1 gene was associated with symptomatic status. We included 46 X-linked adrenoleukodystrophy carriers in a prospective cross-sectional cohort study. Our data show that X-linked adrenoleukodystrophy carriers develop signs and symptoms of myelopathy (29/46, 63%) and/or peripheral neuropathy (26/46, 57%). Especially striking was the occurrence of faecal incontinence (13/46, 28%). The frequency of symptomatic women increased sharply with age (from 18% in women <40 years to 88% in women >60 years of age). Virtually all (44/45, 98%) X-linked adrenoleukodystrophy carriers had increased very long-chain fatty acids in plasma and/or fibroblasts, and/or decreased very long-chain fatty acids beta-oxidation in fibroblasts. We did not find an association between the X-inactivation pattern and symptomatic status. We conclude that X-linked adrenoleukodystrophy carriers develop an adrenomyeloneuropathy-like phenotype and there is a strong association between symptomatic status and age. X-linked adrenoleukodystrophy should be considered in the differential diagnosis in women with chronic myelopathy and/or peripheral neuropathy (especially with early faecal incontinence). ABCD1 mutation analysis deserves a place in diagnostic protocols for chronic non-compressive myelopathy.
Comments [show]
None has been submitted yet.
No. Sentence Comment
141 Table 1 Summary of symptoms and signs of all the female participating in the study Family Age (years) Urinary incontinence Faecal incontinence Gait disorder Sensory complaints Sensory disturbance Spasticity Weakness Pathological reflexes EDSS Mutation ABCD1 protein A 44 No No Yes No No No No Yes 1.0 p.Pro480Thr Absent A 56 Yes Yes No No No No No Yes 1.5 p.Pro480Thr Absent AA 45 No No No No No No No No 0 p.Arg660Trp Absent AA 59 Yes No Yes No No No Yes Yes 3.5 p.Arg660Trp Absent AA 75 Yes No Yes No Yes Yes Yes Yes 6.0 p.Arg660Trp Absent B 42 Yes Yes Yes No Yes Yes Yes Yes 4.0 p.Leu220Pro Reduced B 44 No No No No No No No No 0 p.Leu220Pro Reduced B 44 No No No No No No No No 0 p.Leu220Pro Reduced B 51 No No No Yes Yes No No No 1.0 p.Leu220Pro Reduced B 59 No No No Yes Yes No Yes No 2.0 p.Leu220Pro Reduced C 44 No No No No No No No No 0 p.Gln133* Absent D 38 Yes Yes Yes No Yes Yes Yes Yes 6.0 p.Leu654Pro Absent D 57 Yes No Yes Yes Yes No No Yes 5.5 p.Leu654Pro Absent E 31 No No No No No No No No 0 p.Arg74Trp Absent E 37 No No No No No No No No 0 p.Arg74Trp Absent E 60 No No Yes No Yes Yes Yes Yes 5.5 p.Arg74Trp Absent F 35 No No No No No No No No 0 p.Met1Val Absent G 42 No Yes No No No No No No 1.0 p.Ala245Asp Present H 61 Yes Yes Yes Yes Yes No No Yes 3.5 exon8-10del Absent I 71 No No No No Yes No No Yes 2.0 p.Glu609Lys Absent J 42 No No No No Yes No No Yes 1.5 p.Glu90* Absent K 31 No No No No No No No No 0 p.Pro543Leu Absent K 48 Yes No No No Yes No No Yes 2.5 p.Pro543Leu Absent K 57 No No Yes Yes Yes No Yes Yes 3.5 p.Pro543Leu Absent K 60 Yes No No No Yes No No Yes 3.5 p.Pro543Leu Absent L 51 Yes No Yes No Yes Yes Yes Yes 6.5 p.Ile657del Absent M 22 No No No No No No No No 0 p.Ser149Asn Reduced M 40 No No No No No No No No 0 p.Ser149Asn Reduced N 29 No No No No No No No No 0 p.Arg389His Reduced N 45 Yes No No Yes No No No No 2.0 p.Arg389His Reduced N 57 Yes Yes Yes Yes Yes No No No 3.5 p.Arg389His Reduced N 70 No No Yes No Yes No Yes Yes 3.5 p.Arg389His Reduced O 40 Yes Yes Yes Yes Yes No No Yes 3.5 p.Glu609Lys Absent P 59 Yes Yes Yes Yes Yes Yes Yes Yes 6.0 p.Leu215* Absent Q 39 No Yes Yes No Yes No No No 3.0 p.Val208Trpfs Absent R 28 No No No No No No No No 0 p.Pro480Thr Absent S 35 No No No No No No No No 0 p.His283Tyr Reduced (continued) Correlation studies of X-inactivation with asymptomatic or symptomatic status The distribution of ABCD1 allele-specific expression (which will be referred to as the pattern of X-inactivation) is shown in Fig. 5A.
X
ABCD1 p.Glu609Lys 24480483:141:1330
status: NEWX
ABCD1 p.Glu609Lys 24480483:141:2037
status: NEW