ABCMdb

ABCD1 p.Ser515Tyr

ClinVar:	c.1544C>T , p.Ser515Phe D , Pathogenic
Predicted by SNAP2:	A: D (85%), 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 (95%), P: D (95%), Q: D (95%), R: D (95%), T: D (91%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, 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: D, V: D, W: D, Y: D,

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Publications
[hide] Eight novel mutations in the ABCD1 gene and clinic... World J Pediatr. 2015 Nov;11(4):366-73. doi: 10.1007/s12519-015-0044-0. Epub 2015 Oct 11. Chu SS, Ye J, Zhang HW, Han LS, Qiu WJ, Gao XL, Gu XF
Eight novel mutations in the ABCD1 gene and clinical characteristics of 25 Chinese patients with X-linked adrenoleukodystrophy.
World J Pediatr. 2015 Nov;11(4):366-73. doi: 10.1007/s12519-015-0044-0. Epub 2015 Oct 11., [PMID:26454440]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by mutations in the adenosine triphosphate-binding cassette D1 (ABCD1) gene. This study aimed to retrospectively investigate the clinical characteristics of 25 patients with X-ALD including members of large pedigrees, to analyze ABCD1 gene mutations, the effect of gene novel variants on ALD protein (ALDP) structure and function, and to expand gene mutation spectrum of Chinese patients. METHODS: Twenty-five male patients diagnosed with X-ALD were enrolled in this study. The clinical characteristics of the patients were retrospectively summarized by reviewing medical records or telephone consultation. ABCD1 gene mutations were analyzed. The pathogenicity of novel missense variants was analyzed using cobalt constraint-based multiple protein alignment tool, polymorphism phenotyping, sorting intolerant from tolerant, Align-Grantham variation and Grantham deviation, and Swiss-Program Database Viewer 4.04 software, respectively. RESULTS: Childhood cerebral form ALD (CCALD) is the most common phenotype (64%) in the 25 patients with X-ALD. The progressive deterioration of neurological and cognitive functions is the main clinical feature. The demyelination of the brain white matter and elevated plasma very long chain fatty acids (VLCFAs) were found in all patients. Different phenotypes were also presented within family members of the patients. Twenty-two different mutations including 8 novel mutations in the ABCD1 gene were identified in the 25 patients. Of the mutations, 63.6% were missense mutations and 34.8% located in exon 1. The amino acid residues of three novel missense mutations in eight species were highly conserved, and were predicted to be "probably" damaging to ALDP function. The other five novel mutations were splice, nonsense, deletion or duplication mutations. CONCLUSIONS: CCALD is the most common phenotype (64%) in our patients with X-ALD. Eight novel mutations in the ABCD1 gene identified are disease-causing mutations. Brain magnetic resonance imaging and plasma VLCFA determination should be performed for the patients who present with progressive deterioration of neurological development.

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No. Sentence Comment
86 Eight of the 22 mutations [c.1017G>T (p.W339C), c.892G>C (p.G289R), c.532C>T (p.Q178*), c.1544C>A (p.S515Y), c.1428C>A (p.C476*), c.1182delG (p.A395Lfs*15), c.424delC (p.L142Sfs*56), c.1759_1761dup (p.I588H)] were novel (Fig. 2). Login to comment
111 However, some X-ALD males remain asymptomatic and one-third of heterozygous women remain free of clinical symptoms during their Patient number Exon Nucleotide change Amino acid change Protein localization References P1 2 c.1017G>T p.Trp339Cys TMD Novel P2 8 c.1850G>A p.Arg617His NBD Fanen et al, 1994[12] P4 1 c.892G>C p.Gly298Arg TMD Novel P5, P6 5 c.1415_16delAG p.Gln472Argfs*83 TMD to NBD Barcelo et al, 1994[13] P7 1 c.532C>T p.Gln178* TMD Novel P8 1 c.473T>C p.Leu158Pro TMD The peroxisomal diseases laboratory (unpublished) P10 6 c.1552C>T p.Arg518Trp NBD Fanen et al, 1994[12] P11 3 c.1202G>A p.Arg401Gln TMD to NBD Fuchs et al, 1994[14] P12 1 c.887A>G p.Tyr296Cys TMD Takano et al, 1999[15] P13 1 c.893G>A p.Gly298Asp TMD Lachtermacher et al, 2000[16] P14 1 c.310C>T p.Arg104Cys TMD Kok et al, 1995[17] P15 IVS 8 c.1866-10G>A p.Pro623fs* NBD Kemp et al, 1995[18] P16 5 c.1428C>A p.Cys476* NBD Novel P17 5 c.1421T>C p.Ile474Thr NBD Shimozawa et al, 2011[19] P18 6 c.1538A>G p.Lys513Arg NBD Piti&#e9;-Salp&#e9;tri&#e8;re Hospital (unpublished) P19 1 c.310C>T p.Arg104Cys TMD Kok et al, 1995[17] P20 6 c.1544C>A p.Ser515Tyr NBD Novel P21 2 c.901-1G>A p.Val301fs* TMD Kemp et al, 2001[20] P22 2 c.974T>C p.Leu325Pro TMD The peroxisomal diseases laboratory (unpublished) P23 3 c.1182delG p.Ala395Leufs*15 TMD to NBD Novel P24 1 c.424delC p.Leu142Serfs*56 TMD Novel P25 7 c.1759_1761dup p.Ile588His NBD Novel Table 2. Login to comment
114 Variables P1 P4 P20 cDNA mutations c.1017G>T c.892G>C c.1544C>A Protein level p.Trp339Cys p.Gly298Arg p.Ser515Tyr Conservation Highly conserved Highly conserved Highly conserved Polyphen prediction Probably damaging Probably damaging Probably damaging SIFT prediction Deleterious Deleterious Deleterious Align-GVGD Most likely to interfere with function Most likely to interfere with function Most likely to interfere with function Amino acid location (wild-type residue) A transmembrane domain ABC transmembrane type-1 ABC transporter Amino acid size change (than the wild-type residue) Smaller Bigger Bigger Amino acid physicochemical property change Aromatic amino acids to neutral polar amino acids (hydrophilicity) Non polar aliphatic amino acids to alkaline amino acids Neutral polar amino acids to aromatic amino acids (hydrophilic reduced) Charge characteristic change No Neutral to positive No Form a hydrogen bond with the neighbors No No Yes Influence from the mutant residue Disturb either the contacts with the other transmembrane domains or with the lipid-membrane Change the flexibility of wild-type residue which might abolish protein function The size difference makes that the new residue is not in the correct position and interferes with hydrogen bond Table 3. Login to comment
118 A: c.1017G>T (p.W339C); B: c.892G>C (p.G289R); C: c.532C>T (p.Q178*); D: c.1544C>A (p.S515Y); E: c.1428C>A (p.C476*); F: c.1182delG (p.A395Lfs*15); G: c.424delC (p.L142Sfs*56); H: c.1759_1761dup (p.I588H). Login to comment
121 b1;-Helix is presented in green, b2;-strands is displayed in yellow and coil is marked with gray respectively; B: Change of ALDP structure in three patients with novel missense mutations: c.1017G>T (p.Trp339Cys) in P1, c.892G>C (p.Gly298Arg) in P4, and c.1544C>A (p.Ser515Tyr) in P20. Login to comment
123 A B p.Trp339Cys p.Gly298Arg p.Ser515Tyr entire life. Login to comment