ABCMdb

ABCC9 p.Ile146Asn

Predicted by SNAP2:	A: N (61%), C: N (72%), D: D (66%), E: D (66%), F: D (53%), G: N (66%), H: D (66%), K: D (66%), L: N (93%), M: N (66%), N: D (71%), P: D (63%), Q: D (63%), R: N (57%), S: N (53%), T: N (53%), V: N (97%), W: D (71%), Y: D (53%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: D, F: N, G: N, H: D, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: N, T: N, V: N, W: D, Y: N,

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[hide] Complex Brugada syndrome inheritance in a family h... Basic Res Cardiol. 2014;109(6):446. doi: 10.1007/s00395-014-0446-5. Epub 2014 Oct 24. Beziau DM, Barc J, O'Hara T, Le Gloan L, Amarouch MY, Solnon A, Pavin D, Lecointe S, Bouillet P, Gourraud JB, Guicheney P, Denjoy I, Redon R, Mabo P, le Marec H, Loussouarn G, Kyndt F, Schott JJ, Probst V, Baro I
Complex Brugada syndrome inheritance in a family harbouring compound SCN5A and CACNA1C mutations.
Basic Res Cardiol. 2014;109(6):446. doi: 10.1007/s00395-014-0446-5. Epub 2014 Oct 24., [PMID:25341504]

Abstract [show]
Brugada syndrome (BrS) is characterized by ST-segment elevation in the right precordial leads and is associated with increased risk of sudden cardiac death. We have recently reported families with BrS and SCN5A mutations where some affected members do not carry the familial mutation. We evaluated the involvement of additional genetic determinants for BrS in an affected family. We identified three distinct gene variants within a family presenting BrS (5 individuals), cardiac conduction defects (CCD, 3 individuals) and shortened QT interval (4 individuals). The first mutation is nonsense, p.Q1695*, lying within the SCN5A gene, which encodes for NaV1.5, the alpha-subunit of the cardiac Na(+) channel. The second mutation is missense, p.N300D, and alters the CACNA1C gene, which encodes the alpha-subunit CaV1.2 of the L-type cardiac Ca(2+) channel. The SCN5A mutation strictly segregates with CCD. Four out of the 5 BrS patients carry the CACNA1C variant, and three of them present shortened QT interval. One of the BrS patients carries none of these mutations but a rare variant located in the ABCC9 gene as well as his asymptomatic mother. Patch-clamp studies identified a loss-of-function of the mutated CaV1.2 channel. Western-blot experiments showed a global expression defect while increased mobility of CaV1.2 channels on cell surface was revealed by FRAP experiments. Finally, computer simulations of the two mutations recapitulated patient phenotypes. We report a rare CACNA1C mutation as causing BrS and/or shortened QT interval in a family also carrying a SCN5A stop mutation, but which does not segregate with BrS. This study underlies the complexity of BrS inheritance and its pre-symptomatic genetic screening interpretation.

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129 The J point elevation and the coved type ST-segment elevation observed in high precordial lead (V1H, V2H, V3H recorded at the third ICS) remained significant after the test and after correction of conduction disturbance Table 1 Clinical and genetic data of the family members ID Age (year) Basal ECG ECG during ajmaline challenge Genetic results PR (ms) QRS (ms) QT (ms) QTc (ms) T-wave aspect QRS aspect ST-segment amplitude (mm) ST-segment aspect Result of the ajmaline challenge PR (ms) QRS (ms) ST-segment amplitude (mm) ST-segment aspect SCN5A CACNA1C ABCC9 I-2 85 160 80 360 412 Normal Normal 0 Normal 0 NA NA NA NA NC NC I146N II-1 62 180 95 340 350 Tall Normal 0 Normal Negative 200 120 0 Normal NC N300D NC II-2 49 138 70 318 385 Normal Normal 0 Normal Positive 171 104 6 Coved NC NC I146N II-3 52 200 100 322 347 Normal Normal 0 Normal Positive 270 120 3 Coved NC N300D NC II-4 57 200 120 368 385 Normal Normal 0 Normal Negative 200 120 0 Normal Q1695* NC NC III-1 26 200 120 380 370 Normal Parietal bloc 1 Saddle back Positive 220 200 3 Coved Q1695* N300D NC III-2 23 206 108 351 347 Tall Normal 1 Normal Positive 240 200 3 Coved Q1695* N300D NC III-3 20 140 95 340 340 Tall Normal 0 Normal Positive 200 110 10 Coved NC N300D NC III-4 19 140 80 335 348 Tall Normal 0 Normal Negative 160 90 2 Saddle back NC N300D NC NA not available, NC non carrier Fig. 2 a Pedigree, phenotype and genotype of the family. Login to comment
148 In this patient, we found a rare SNP (rs149325742, MAF = 0.0077 %) corresponding to the substitution of A[T at the position chr12:22070007, leading to an amino acid changing an isoleucine to an asparagine in position 146 (p.I146N). Login to comment