ABCMdb

ABCA13 p.Thr4031Ala

Predicted by SNAP2:	A: D (91%), C: D (53%), D: D (53%), E: N (57%), F: D (66%), G: D (59%), H: N (61%), I: D (53%), K: N (66%), L: D (59%), M: N (53%), N: N (66%), P: D (59%), Q: N (53%), R: N (53%), S: N (72%), V: N (53%), W: D (80%), Y: D (63%),
Predicted by PROVEAN:

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[hide] Investigation of rare non-synonymous variants at A... Mol Psychiatry. 2011 Aug;16(8):790-1. doi: 10.1038/mp.2011.2. Epub 2011 Feb 1. Dwyer S, Williams H, Jones I, Jones L, Walters J, Craddock N, Owen MJ, O'Donovan MC
Investigation of rare non-synonymous variants at ABCA13 in schizophrenia and bipolar disorder.
Mol Psychiatry. 2011 Aug;16(8):790-1. doi: 10.1038/mp.2011.2. Epub 2011 Feb 1., [PMID:21283083]

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24 Two bipolar cases and two controls were heterozygous for T4031A and T4550A. Login to comment

[hide] A cytogenetic abnormality and rare coding variants... Am J Hum Genet. 2009 Dec;85(6):833-46. Epub . Knight HM, Pickard BS, Maclean A, Malloy MP, Soares DC, McRae AF, Condie A, White A, Hawkins W, McGhee K, van Beck M, MacIntyre DJ, Starr JM, Deary IJ, Visscher PM, Porteous DJ, Cannon RE, St Clair D, Muir WJ, Blackwood DH
A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.
Am J Hum Genet. 2009 Dec;85(6):833-46. Epub ., [PMID:19944402]

Abstract [show]
Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of approximately 80% indicating a substantial genetic component. Population genetics and genome-wide association studies suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, we resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including one nonsense and nine missense mutations and compound heterozygosity/homozygosity in six cases. Variants were genotyped in additional schizophrenia, bipolar, depression (n > 1600), and control (n > 950) cohorts and the frequency of all rare variants combined was greater than controls in schizophrenia (OR = 1.93, p = 0.0057) and bipolar disorder (OR = 2.71, p = 0.00007). The population attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, we genotyped affected and unaffected relatives and found significant linkage (LOD = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. These data identify a candidate gene, highlight the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggest that rare coding variants may contribute significantly to risk of these disorders.

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91 Despite relatively small numbers, three variants (H3609P, T4031A, and T4550A) were significantly more frequent in bipolars than controls and R4843L was more common in schizophrenia (Table 2), although none remained significant after correction for multiple testing of 10 variants in three phenotypes. Login to comment
100 All ABCA13 Variants with Provisional dbSNP Identifiers Identified during the Resequencing Discovery Stage of This Study Domain Chr7 Location bp NCBI Build 36.1 Base Change dbSNP Reference AA Change Substitution Type MAF Cases MAF controls Discovery Populationa TMD1 48,382,318 G/A ss136294996 R3604Q missense A: 0.0003 A: 0.0005 case TMD1 48,382,333 A/C ss136295002 H3609P missense C: 0.0085 C: 0.0043 both TMD1 48,382,337 A/C ss136295006 P3610P synonymous C: 0.0096 C: 0.0000 case TMD1 48,382,337 A/T ss136295010 P3610P synonymous T: 0.0048 T: 0.0037 both TMD1 48,382,619 T/G ss136295014 S3704R missense/splice variant G: 0.0003 G: 0.0000 case TMD1 48,384,364 C/T ss136295018 intronic T: 0.0095 T: 0.0160 both TMD1 48,384,474 A/G ss136295022 intronic G: 0.0045 G: 0.0000 case TMD1 48,384,623 T/C ss136295026 intronic C: 0.0048 C: 0.0053 both TMD1 48,398,156 G/A ss136295030 intronic A: 0.0523 nd case TMD1 48,398,232 G/C ss136295034 intronic C: 0.0048 nd case NBD1 48,399,292 C/G ss136295038 L3861L synonymous G: 0.0000 G: 0.0052 control NBD1 48,399,322 T/C ss136295042 T3871T synonymous C: 0.0000 C: 0.0052 control NBD1 48,413,738 C/T ss136295046 intronic T: 0.0092 nd case NBD1 48,420,643 C/T ss136295050 intronic T: 0.1651 T: 0.2067 both NBD1 48,420,683 A/G ss136295054 T4031A missense G: 0.0009 G: 0.0000 case NBD1 48,420,731 C/G ss136295058 L4047V missense (>1% frequency) G: 0.0169 G: 0.0104 both NBD1 48,420,834 C/G ss136295062 intronic G: 0.1651 G: 0.2067 both HDR 48,465,394 T/C ss136295066 P4260P synonymous C: 0.0000 C: 0.0052 control HDR 48,465,399 A/G ss136295070 H4262R missense G: 0.0003 G: 0.0000 case TMD2 48,518,027 C/T ss136295074 R4454C missense (>1% frequency) T: 0.0142 T: 0.0156 both TMD2 48,518,057 C/A ss136295078 L4464M missense (>1% frequency) A: 0.0095 A: 0.0208 both TMD2 48,526,874 A/G ss136295082 T4550A missense A: 0.0056 A: 0.0014 case TMD2 48,526,994 C/T ss136295086 R4590W missense T: 0.0044 T: 0.0019 control TMD2 48,527,112 C/G ss136295090 intronic G: 0.0286 G: 0.0161 both TMD2 48,530,327 C/G ss136295094 P4648A missense G: 0.0000 G: 0.0004 control NBD2 48,534,459 A/G ss136295098 R4707R synonymous G: 0.0500 G: 0.0526 both NBD2 48,534,520 C/T ss136295102 R4728X nonsense T: 0.0025 T: 0.001 case NBD2 48,538,544 C/T ss136295106 intronic T: 0.0000 T: 0.0153 control NBD2 48,538,545 C/T ss136295110 intronic T: 0.0000 T: 0.0052 control NBD2 48,597,311 A/G ss136295114 I4841V missense G: 0.0040 G: 0.0000 case NBD2 48,597,317 C/T ss136295118 R4843C missense T: 0.0050 T: 0.0031 control NBD2 48,604,841 C/A ss136295122 intronic A: 0.0519 A: 0.0789 both The genomic and functional domain location of the variants is displayed together with mutation class and frequency in the discovery set. Login to comment
104 The Properties of Ten Rare ABCA13 Variants Genotyped in Large Test Cohorts of Cases and Controls Representation in Discovery Set Representation in Test Set SCZ BP MDD Variant Domain Exon Genomic Position Base Change WT Residue Conservation Residue Change Type SCZ (n ¼ 100) Controls (n ¼ 100) Cases (total) Cases by Diagnosis (Total) Controls (Total) p Value Odds Ratio p Value Odds Ratio p Value Odds Ratio 1 TMD1 33 48,382,318 G/A RH, D, R, M, R3604Q missense 1 0 0 (1666) 0/841 SCZ, 0/494 BP, 0/331 MDD 1 (951) 2 TMD1 33 48,382,333 A/C RH, D, R, M, Ch H3609P missense 3 1 25 (1607) 10/857 SCZ, 10/488 BP, 5/262 MDD 8 (939) 0.334 1.37 0.050 2.43 0.130 2.62 3 TMD1 33 48,382,619 T/G RH, D, R, M, Ch S3704R miss./splice 1 0 0 (1606) 0/851 SCZ, 0/496 BP, 0/259 MDD 0 (939) 4 NBD1 40 48,420,683 A/G RH, D, R, M, Ch T4031A missense 1 0 3 (2072) 0/1019 SCZ, 3/678 BP, 0/365 MDD 0 (2262) 0.012 infinity 5 HDR 43 48,465,399 A/G RH, R, M, Ch H4262R missense 1 0 0 (1717) 0/837 SCZ, 0/562 BP, 0/318 MDD 0 (980) 6 TMD2 52 48,526,874 A/G RH, D, R, Ch T4550A missense 1 0 18 (1608) 9/861 SCZ, 8/482 BP, 1/265 MDD 3 (938) 0.054 3.29 0.0097 5.25 0.63 1.18 7 TMD2 52 48,526,994 C/T RH, D, R, M, Ch R4590W missense 0 1 17 (1846) 6/874 SCZ, 7/622 BP, 4/350 MDD 4 (971) 0.38 1.5 0.087 2.75 0.14 2.78 8 TMD2 53 48,530,327 C/G RH, D, R, M, Ch P4648A missense 0 1 0 (1488) 0/869 SCZ, 0/619 BP 0 (959) 9 NBD2 54 48,534,520 C/T RH, D, R, M, Ch R4728X nonsense 1 0 10 (2058) 4/1004 SCZ, 5/680 BP, 1/374 MDD 5 (2270) 0.370 1.51 0.057 3.35 0.600 1.21 10 NBD2 57 48,597,317 C/T RH, D, R, M, Ch R4843C missense 0 1 19 (1770) 12/815 SCZ, 5/619 BP, 2/336 MDD 6 (1025) 0.047 2.54 0.400 1.38 0.630 1.02 Global significance of all variants by diagnosis (95% CI lower limit shown for odds ratios): 5.70E- 03 1.93 (1.24) 7.42E- 05 2.71 (1.73) 9.66E- 02 1.67 (0.88) Population attributable risk by diagnosis: 2.21% 4.00% 0.02% 838TheAmericanJournalofHumanGenetics85,833-846,December11,2009 Nonparametric single point linkage analysis with MERLIN50 to estimate identity by descent (IBD) between all pairs of affected relatives in the 14 multiply affected families informative for linkage gave a combined Z score of 4.18 and a Kong and Cox51 LOD score of 4.38 (p ¼ 3.5 3 10À6 ), establishing significant linkage of ABCA13 mutations with a ''broad`` phenotype that included cases with schizophrenia, bipolar disorder, and major depression. Login to comment
107 Figure 3 highlights the sequence conservation and structural consequences of the potential null mutations R4728X and S3704R and missense mutation T4031A. Login to comment
124 T4031A, a missense variant located in NBD1 (Figures 3B and 3E), was identified in three individuals with bipolar pValueOdds Ratio Globalsignificanceofallvariantsacrossalldiagnoses(95%CIlowerlimitshownforoddsratio):2.60E-042.1 (1.45) Populationattributableriskacrossalldiagnoses:2.61% Thegenomiclocation,natureofthenucleotidemutation,resultingaminoacidchange,andcross-speciesconservationofthewild-typeresiduearelisted.Thestatisticalsignificance(significantpvalueshighlightedinbold type),oddsratio,andpopulationattributableriskforindividualandgrouped(globalassessment)variantsaredetailedinrelationtotheirfrequencyintheindividualandcombinedcaseandcontrolgroupings.Inconjunction withpathologicalpredictionandfamilydata,onlyP4648Afailedtoshowevidenceforacausalroleinpsychiatricillness.GenomicpositionbasedonNCBIbuild36.1.pvaluescalculatedbyFisher`sexacttest(one-tailed) excludingvariantcountsfromthediscoveryschizophreniaandcontrolsets.CI,confidenceinterval.Abbreviations:SCZ,schizophrenia;BP,bipolardisorder;MDD,majordepressivedisorder;NBD,nucleotidebindingdomain; TMD,transmembranedomainclusters;HDR,hydrophobicdippingregion.Conservationabbreviations:RH,rhesusmonkey;D,dog;R,rat;M,mouse;Ch,chicken. Login to comment
128 T4031A is strictly conserved across species and among all human ABCA NBD1s (Figure 3E; Figure S1), and we evaluated the consequence of the mutation on protein structure and function by means of a comparative three-dimensional model (Material and Methods; Figures 3G and 3H). Login to comment
151 The mutation showed incomplete penetrance and was found on a distinct haplotype background (as T4031A, see above) (Table S4). Login to comment
160 Two of the four cases with T4031A, one with schizophrenia and one bipolar, were compound Figure 3. Login to comment
161 Characterization of the R4728X, T4031A, and S3704R Rare Variants (A-C) Sequence of wild-type (top) and heterozygous (bottom) alleles for variants R4728X (A), T4031A (B), and S3704R (C). Login to comment
162 (D-F) The wild-type residues are highly conserved within the ABCA family of proteins and between species orthologs for T4031A and S3704R (E, F) but less so for R4728X (D), which most likely reflects its different mode of pathological action (hs, Homo sapiens; mm, Mus musculus; gg, Gallus gallus). Login to comment
164 The side chains of ATP-binding motifs are shown (Walker A, cyan; Walker B, blue; Q-loop, light brown; H-loop, pink; D-loop, magenta; C-loop, red) and mutated residue T4031A (green). Login to comment
172 Only one relative of the two compound heterozygotes was available for study and this unaffected parent of the proband with schizophrenia carried only T4031A. Login to comment
134 T4031A is strictly conserved across species and among all human ABCA NBD1s (Figure 3E; Figure S1), and we evaluated the consequence of the mutation on protein structure and function by means of a comparative three-dimensional model (Material and Methods; Figures 3G and 3H). Login to comment
157 The mutation showed incomplete penetrance and was found on a distinct haplotype background (as T4031A, see above) (Table S4). Login to comment
166 Two of the four cases with T4031A, one with schizophrenia and one bipolar, were compound Figure 3. Login to comment
167 Characterization of the R4728X, T4031A, and S3704R Rare Variants (A-C) Sequence of wild-type (top) and heterozygous (bottom) alleles for variants R4728X (A), T4031A (B), and S3704R (C). Login to comment
168 (D-F) The wild-type residues are highly conserved within the ABCA family of proteins and between species orthologs for T4031A and S3704R (E, F) but less so for R4728X (D), which most likely reflects its different mode of pathological action (hs, Homo sapiens; mm, Mus musculus; gg, Gallus gallus). Login to comment
170 The side chains of ATP-binding motifs are shown (Walker A, cyan; Walker B, blue; Q-loop, light brown; H-loop, pink; D-loop, magenta; C-loop, red) and mutated residue T4031A (green). Login to comment
178 Only one relative of the two compound heterozygotes was available for study and this unaffected parent of the proband with schizophrenia carried only T4031A. Login to comment

[hide] The effects of neurological disorder-related codon... Biosci Biotechnol Biochem. 2012;76(12):2289-93. Epub 2012 Dec 7. Tomioka M, Toda Y, Kurisu J, Kimura Y, Kengaku M, Ueda K
The effects of neurological disorder-related codon variations of ABCA13 on the function of the ABC protein.
Biosci Biotechnol Biochem. 2012;76(12):2289-93. Epub 2012 Dec 7., [PMID:23221702]

Abstract [show]
Rare coding variants of ATP-binding cassette protein A13 (ABCA13) contribute to the risk of neurological disorders, but little is known about the physiological function of ABCA13 and how single nucleotide polymorphisms (SNPs) affect it. Here, we examined the effects of neurological disorder-related SNPs ABCA13, T4031A and R4843C in the context of ABCA1, and found that the former SNP (T1088A in ABCA1) severely impaired the ABCA1 functions of apolipoprotein A-I (apoA-I) binding and cholesterol efflux. The antibody against mouse ABCA13 reacted with neurons in the cerebral cortex, hippocampus, and cerebellum. These results suggest that the T4031A replacement affects the function of ABCA13 in the brain.

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1 Here, we examined the effects of neurological disorder-related SNPs ABCA13, T4031A and R4843C in the context of ABCA1, and found that the former SNP (T1088A in ABCA1) severely impaired the ABCA1 functions of apolipoprotein A-I (apoA-I) binding and cholesterol efflux. Login to comment
3 These results suggest that the T4031A replacement affects the function of ABCA13 in the brain. Login to comment
16 Two SNPs of ABCA13, T4031A and R4843C, were inserted into the corresponding amino acid residues of ABCA1, T1088A and K2031C. Login to comment
81 Detection of ABCA13 in the mouse brain The above results suggest that SNP T4031A, reported to be linked with risk of neurological disorder, can Fig. 4. Login to comment
97 Discussion In this study, we examined the effects of neurological disorder-related SNPs of ABCA13, T4031A, and R4843C, in the context of ABCA1, and found that the former SNP severely impaired ABCA1 function. Login to comment
98 Because the antibody against ABCA13 reacted with neuronal cells in the cerebral cortex, hippocampus, and cerebellum, T4031A replacement in ABCA13 could affect its function in neurons. Login to comment
82 Detection of ABCA13 in the mouse brain The above results suggest that SNP T4031A, reported to be linked with risk of neurological disorder, can Fig. 4. Login to comment
99 Because the antibody against ABCA13 reacted with neuronal cells in the cerebral cortex, hippocampus, and cerebellum, T4031A replacement in ABCA13 could affect its function in neurons. Login to comment