ABCMdb

ABCA13 p.Ser3704Arg

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Publications

PMID: 19944402 [PubMed] Knight HM et al: "A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression."

No. Sentence 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
118 S3704R, located in an extracellular loop of the first TMD (Figures 3C and 3F) was found in a subject with schizophrenia in the discovery cohort and cosegregated with schizophrenia (one case) and depression (four cases) in the proband`s family (Fam10). Login to comment
122 Hence, S3704R displays the features of a rare Mendelian, highly penetrant, deleterious mutation. 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
197 A second type of variant (mostly missense mutations), have higher frequencies of up to 2%-3% in the case population, ORs of 2 or more, and tend to show less familial aggregation.82 In the present study S3704R conforms to the first class of null private mutation with high penetrance and low frequency whereas the missense mutations H3609P, T4550A, and R4590W show characteristics more typical of the second class by virtue of also being detected in controls, having moderate ORs, and higher observed frequencies. 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
203 A second type of variant (mostly missense mutations), have higher frequencies of up to 2%-3% in the case population, ORs of 2 or more, and tend to show less familial aggregation.82 In the present study S3704R conforms to the first class of null private mutation with high penetrance and low frequency whereas the missense mutations H3609P, T4550A, and R4590W show characteristics more typical of the second class by virtue of also being detected in controls, having moderate ORs, and higher observed frequencies. Login to comment