ABCMdb

PMID: 16429405

Fernandez-Marmiesse A, Salas A, Vega A, Fernandez-Lorenzo JR, Barreiro J, Carracedo A
Mutation spectra of ABCC8 gene in Spanish patients with Hyperinsulinism of Infancy (HI).
Hum Mutat. 2006 Feb;27(2):214., [PubMed]

Sentences

No. Mutations Sentence Comment

106 ABCC8 p.Asn188Ser ABCC8 p.Gly111Arg ABCC8 p.Arg74Trp Mutations c.220C>T (p.R74W), c.331G>C (p.G111R), and c.563A>G (p.N188S) are situated in the TMD0 domain of SUR1 which is implicated in the strong association between SUR1 and Kir6.2 and modulate trafficking and gating of the channel (Chan et al. 2003). Login to comment 107 ABCC8 p.Arg74Trp ABCC8 p.Arg74Gln Although R74W was found for first time in our population, Nestorowicz et al. (1998) described a different amino acid change at the same codon (R74Q). Login to comment 108 ABCC8 p.Gly111Arg It was recently demonstrated that the second substitution G111R constitutes a pathological change (Tornovsky et al 2004). Login to comment 109 ABCC8 p.Asn188Ser Finally, mutation N188S detected in homozygosis in patient P25 had been previously reported by Nestorowicz et al. (1998) associated with severe clinical disease, although it was reported by Shyng et al. (1998), that this mutation alters channel function only minimally in vitro. Login to comment 111 ABCC8 p.Asn188Ser This substitution appears as a pathogenic mutation in the Human Gene Mutation Database which seems to support that N188S produces a non pathogenic change. Login to comment 112 ABCC8 p.Asp310Asn ABCC8 p.Met233Arg The second sets of missense mutations (c.698T>G (p.M233R) and c.928G>A (p.D310N)) are placed in the CL3 domain of SUR1, also implicated in modulate gating of the channel (Babenko et al 2003). Login to comment 114 ABCC8 p.Lys719Thr The amino acid change c.2156A>C (p.K719T) is positioned in the cytoplasmatic domain CL6 (NBF1) of SUR1 and constitutes a highly conserved residue. Login to comment 115 ABCC8 p.Lys719Pro It was previously described a mutation which affected the same codon and promoted the change K719P (Gribble et al. 1997) and functional experiments showed that it provoked a reduced response to ADP-Mg. Login to comment 137 ABCC8 p.Asp310Asn ABCC8 p.Asn188Ser ABCC8 p.Asn188Ser ABCC8 p.Gly111Arg ABCC8 p.Arg74Trp ABCC8 p.Arg598* ABCC8 p.Met233Arg ABCC8 p.Lys719Thr ABCC8 p.Pro551Arg ABCC8 p.Arg248* ABCC8 p.Arg248* ABCC8 p.Leu1148Arg Clinical characteristics of HI Spanish patients that carry at least one mutation in ABCC8 Mutationsg Pa Ob Sex Mc Td PCe PTf Pchrh Mchrh 1a Gal M >p90 DZ 5 (>90%) OT, NF, GC p.R248X c.3576delG 1b Gal F >p50 DZ, OT, NF - OT, NF, NGT p.R248X c.3576delG 3 Gal F >p90 DZ 2 (95%) - c.584 585insA c.584 585insA 4 Gal M >p75 DZ 4 (95%) DZ, NGT c.584 585insA c.584 585insA 5 Gal M >p50 OT, DZ 16 (90%) - c.1347 1348delGA - 8 Cast M >p75 DZ, OT, GC - - p.M233R - 9 Cast F >p75 DZ 0.5 (85%) DZ, OT, PC (99%) p.G111R - 12 And M - - - - c.4612 -2 A>T p.D310N 14 Cat M >p75 DZ - - p.R934X c.3992-9 G>A 17 Cat F >p90 DZ, OT - - c.3133 3152del c.4619 4620insT 18 Cat M <p50 DZ, CNF 0.5 (95%) DZ c.1732 1746dup - 19 Can M <p50 DZ, NF, OT 2 (99%) - c.1332+4438 1631-9207del c.1332+4438 1631-9207del 20 Cat M - DZ, NF, GC - - c.2142delG p.T1131P 21 Cat F >p50 DZ, NF - - - i - i 23 Bal M >p90 CNF - - c.4310 G>A c.1732 1746dup 25 Mor M - DZ, OT yes (EXITUS) p.N188S, c.4123-19 C>T p.N188S, c.4123-19 C>T 27 Cast F >p75 DZ, CNF 24 (75%) PC (99%) p.R598X p.L1451P 28 Cat M >p90 DZ, CNF - - p.R1251X p.L1148R 30 Cast M >p90 DZ, OT 5 (95%) DZ, OT (EXITUS) p.R74W - 31 Gal F >p90 DZ 0.5 (95%) DZ - p.K719T 32 Cat F >p90 DZ - - - p.N1296K 33 Cast F >p75 DZ, OT 1 (95%) DZ, OT c.3291 3292delGC - 34 Val F >p90 DZ, NF - (EXITUS) p.P551R - a P = patient. Login to comment 147 ABCC8 p.Asp310Asn ABCC8 p.Asn188Ser ABCC8 p.Gly111Arg ABCC8 p.Arg74Trp ABCC8 p.Arg598* ABCC8 p.Met233Arg ABCC8 p.Lys719Thr ABCC8 p.Pro551Arg ABCC8 p.Arg248* ABCC8 p.Leu1148Arg ABCC8 p.Tyr195* Genetic variants found in ABCC8 gene from HI Spanish cohort Mutations considered pathogenic nt change a aa change a Type E/Ic Domaind Patient Refe PSIC f Polypheng C h c.220C>T p.R74W MIS E2 CL1 P30 NR 2.257 PrD Highly c.331G>C p.G111R MIS E3 TM3 P9 [1] 1.672 PsD Moderately c.563A>G p.N188S MIS E4 TM5 P25 [2] 1.494 Benign Highly c.698T>G p.M233R MIS E5 CL3 P8 NR 2.428 PrD Highly c.584_585insA p.Y195X FS E5 ─ P3, P4 NR ─ ─ ─ c.742C>T p.R248X NON E5 ─ P1a, P1b [3] ─ ─ ─ c.928G>A p.D310N MIS E6 CL3 P12 NR 1.614 PsD Highly c.1347_1348delGA p.V449VfsX493 FS E9 ─ P5 NR ─ ─ ─ c.1332+4438_1631-9207del p.I445FfsX447 FS ─ ─ P19 NR ─ ─ ─ c.1652C>G p.P551R MIS E11 TM10 P34 NR 2.1 PsD Highly c.1732_1746dup p.A578_L582dup IFins E12 ─ P18, P23 NR ─ ─ ─ c.1792C>T p.R598X NON E12 ─ P27 NR ─ ─ ─ c.2156 A>C p.K719T MIS E16 CL6 P31 NR 1.927 PsD Highly c.2142delG p.Q714QfsX724 FS E16 ─ P20 NR ─ ─ ─ c.2394-2A>G ─ AS I19 ─ P21 NR ─ ─ ─ c.2800C>T p.R934X NON E23 ─ P14 NR ─ ─ ─ c.3133_3152del p.L1045LfsX1107 FS E25 ─ P17 [6] ─ ─ ─ c.3291_3292delGC p.L1097LfsX1113 FS E26 ─ P33 NR c.3391A>C p.T1131P MIS E27 CL7 P20 NR 1.777 PsD Moderately c.3443T>G p.L1148R MIS E28 TM14 P28 NR 1.722 PsD Highly c.3576delG p.L1191LfsX1207 FS E29 ─ P1a, P1b, NR ─ ─ ─ c.3751C>T p.R1251X NON E30 ─ P28 NR ─ ─ ─ c.3888C>G p.N1296K MIS E32 TM17 P32 NR 1.924 PsD Highly c.3992-9G>A ─ AS I 32 ─ P14 [4] ─ ─ ─ c.4123-19C>T ─ AS I33 ─ P25 [5] ─ ─ ─ c.4310G>A ─ AS E35 ─ P23 [4] ─ ─ ─ c.4352T>C p.L1451P MIS E36 CL9 P27 NR 1.797 PsD Highly c.4612-2 A>T ─ AS I38 ─ P12 NR ─ ─ ─ c.4619_4620insT p.H1540AfsX1559 FS E39 ─ P17 NR ─ ─ ─ Polimorphisms and unclassified variants nt change a aa change a Type E/Ic SNPid Patientsi Controls NCBI j Exclusion c. 207T>C p.P69P SYN E2 rs1048099 28/46 ─ 0.50 S c. 330C>T p.A110A SYN E3 rs8192695 2/48 ─ 0.04 S c. Login to comment 166 ABCC8 p.Asn188Ser ABCC8 p.Gly111Arg ABCC8 p.Lys719Thr ABCC8 p.Leu1148Arg ESEfinder score change of some variants of ABCC8 gene nt change aa change ESE changes a SF2-ASF SC35 SRp40 SRp55 Mutations c.220C>T R74W Lost 2.9 Gain 0.64 Gain 1.49 Lost 1.55 c.331G>C G111R M 2.58 - - - c.563A>G N188S - M 0.36 - Gain 0.61 c.2156 A>C K719T - - - Gain 2.14 c.3391A>C T1131P Lost 1.74 c.3443T>G L1148R M +2.12 Gain 2.39 c.3888C>G N1296K ─ ─ Lost 1.73 ─ c.4352T>C L1451P M -0.42 Lost 0.65 Gain 1.54 ─ Polymorphisms and unclassified variants c. 207T>C P69P Gain 1.458 M -0.645 ─ ─ c. 330C>T A110A M -2.524 ─ ─ ─ c. 1686C>T H562H ─ Lost-0.645 M -0.356 M +1.551 c. 1707C>T* A569A Lost 2.397 ─ ─ ─ c. 1947G>A K649K ─ ─ Lost 0.846 M -0.609 c. 2280C>T T760T Lost 2.524 ─ M +0.356 ─ c. 3822G>A R1274R M -2.824 Lost 2.382 ─ c. 4108T>G S1370A ─ M +0.648 ─ ─ c. 4717G>A V1573I ─ ─ M -0.609 a Lost (or gain) of an ESE below (above) the threshold values (SF2-ASF = 1.956; SC35 = 2.383; SRp40 = 2.67; SRp55 =2.676; Cartegni et al. 2003) are indicated. Login to comment