ABCMdb

PMID: 17919176

Patch AM, Flanagan SE, Boustred C, Hattersley AT, Ellard S
Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period.
Diabetes Obes Metab. 2007 Nov;9 Suppl 2:28-39., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCC8 p.Leu135Pro ABCC8 p.Leu438Phe ABCC8 p.Arg306His Results: We identified ABCC8 mutations in an additional nine probands (including five novel mutations L135P, R306H, R1314H, L438F and M1290V), bringing the total of reported families to 48. Login to comment 83 ABCC8 p.Leu135Pro ABCC8 p.Leu438Phe ABCC8 p.Arg306His Five novel mutations were identified: L135P (c.404T>C), R306H (c.917G>A), R1314H (c.3941G>A), L438F (c.1312C>T) and M1290V (c.3868A>G). Login to comment 85 ABCC8 p.Val86Ala ABCC8 p.Phe132Leu ABCC8 p.Asp212Ile Five residues are sites for different amino acid substitutions: V86A/G, F132L/V, D212I/N, R1183Q/W and R1380C/H/L. Login to comment 86 ABCC8 p.Phe132Leu ABCC8 p.Asp209Glu ABCC8 p.Thr229Ile ABCC8 p.Leu582Val Nine mutations were observed in more than one proband; R1183W (c.3547C>T) was identified in five probands, R1380C (c.4138C>T) in three probands and the remainder; F132L (c.394T>C), D209E (c.627C>A), T229I (c.686C>T), L582V (c.1744C>G), R826W (c.2476C>T), R1183Q (c.3548G>A) and R1380L (c.4139G>T) were each observed in two probands. Login to comment 90 ABCC8 p.Leu135Pro We report two new families with PNDM, a novel, de novo L135P mutation (ISPAD146) and one with recessive inheritance (ISPAD142). Login to comment 96 ABCC8 p.Leu438Phe Compound heterozygous mutations that cause neonatal diabetes were first described in five families by Ellard et al. [14], and a further family is reported here (two affected siblings who are compound heterozygotes for the novel L438F and M1290V mutations; ISPAD142). Login to comment 102 ABCC8 p.Leu135Pro ABCC8 p.Leu438Phe ABCC8 p.Leu438Phe ABCC8 p.Leu438Phe ABCC8 p.Arg306His ABCC8 p.Arg306His ABCC8 p.Arg306His - 126 NA N/NR1380L/N 33 yrs 25 yrs - - R1380L/N 59 yrs 30 yrs - - P NA N/N L438F/M1290V 14 yrs 12 wks - - L438F/N 142 M1290V/N L438F/M1290V 12 yrs 14 wks - - P P R306H/N 65 yrs 51 yrs - - R306H/N 2 yrs 1 wk - - N/N 141 N/N R306H/N 35 yrs - - - N/N P R1314H/N 12 yrs <1 wks 3 wks 11 yrs N/N 144 R1314H/N 36 yrs - - - NA R1380L/N 9 yrs 6 wks - - P R1380L/N 29 yrs 21 yrs - - 145 P L135P/N 10 yrs 6 wks - - N/N N/N 146 P R826W/N 8 yrs 22 wks ? Login to comment 103 ABCC8 p.Thr229Ile ABCC8 p.Thr229Ile - N/N 147 R826W/N NK T229I/T229I 3 yrs ? Login to comment 104 ABCC8 p.Thr229Ile 1 yrs 4 yrs NA 62 T229I/N P Fig. 1 Partial pedigrees for newly identified families showing inheritance of ABCC8 mutations. Login to comment 148 ABCC8 p.Tyr263Asp [14] 119E208Kþ Y263D [c.622G>A]þ [c.787T>G] Compound heterozygous PNDMCanada132950(28)Developmental delay YesEllardetal. Login to comment 149 ABCC8 p.Val1523Leu [14] 120T229Iþ V1523L [c.686C>T]þ [c.4567G>T] Compound heterozygous PNDMCanada4N/AYesEllardetal. Login to comment 151 ABCC8 p.Val1523Ala [14] 121[E1327K; V1523A]þ T1043QfsX74 [c.3979G>A; 4568C>T]þ[c.3127_ 3129delACCinsCA GCCAGGACCTG] Compound heterozygous PNDMUSA12380(<1)Ellardetal. Login to comment 155 ABCC8 p.Thr229Ile previously reported mutations R826W, R1183W and R1380L [18] and the first case of a homozygous mutation (T229I) causing TNDM (ISPAD62). Login to comment 161 ABCC8 p.Val86Ala ABCC8 p.Phe132Leu ABCC8 p.Leu135Pro ABCC8 p.Leu438Phe ABCC8 p.Arg306His ABCC8 p.Asp212Ile ABCC8 p.Asp209Glu ABCC8 p.Asp209Glu ABCC8 p.Thr229Ile ABCC8 p.Thr229Ile ABCC8 p.Thr229Ile ABCC8 p.Leu582Val ABCC8 p.Tyr263Asp ABCC8 p.Val1523Leu ABCC8 p.Asn72Ser ABCC8 p.Cys435Arg ABCC8 p.Val86Gly ABCC8 p.Leu451Pro ABCC8 p.Glu382Lys ABCC8 p.Glu382Lys ABCC8 p.Leu213Arg ABCC8 p.Val324Met ABCC8 p.Glu208Lys ABCC8 p.Phe132Val ABCC8 p.Pro207Ser ABCC8 p.Pro45Leu ABCC8 p.Asp212Asn Affected probands and family members can be separated into three distinct groups based T229I/T229I ABCC8 mutations Transient Neonatal Diabetes Mellitus Recessive homozygous mutations R826W (2) H1024Y R1183Q (2) R1183W (5) R1314H R1380C (3) R1380H R1380L (2) D209E D212I D212N R306H V324M C435R L451P L582V (2) Dominant heterozygous mutations Permanent Neonatal Diabetes Mellitus E382K/E382K A1185E/A1185E Mosaic N72S Recessive homozygous or mosaic mutations P45L/G1401R E208K/Y263D T229I/V1523L L438F/M1290V P207S/c.536del4 E1327K+V1523A/ c.1327ins10 Recessive compound heterozygous mutations 1K Dominant heterozygous mutations D209E Q21 L213R L225P(2) I1425V V86A V86G F132L (2) F132V L135P Fig. 2 A diagram illustrating the inheritance of ABCC8 mutations in probands with permanent and transient forms of neonatal diabetes. Login to comment 163 ABCC8 p.Val86Ala ABCC8 p.Phe132Leu ABCC8 p.Leu438Phe ABCC8 p.Arg306His ABCC8 p.Asp212Ile ABCC8 p.Asp209Glu ABCC8 p.Asp209Glu ABCC8 p.Thr229Ile ABCC8 p.Thr229Ile ABCC8 p.Leu582Val ABCC8 p.Tyr263Asp ABCC8 p.Val1523Leu ABCC8 p.Val1523Ala ABCC8 p.Asn72Ser ABCC8 p.Val86Gly ABCC8 p.Leu451Pro ABCC8 p.Glu382Lys ABCC8 p.Leu213Arg ABCC8 p.Val324Met ABCC8 p.Glu208Lys ABCC8 p.Phe132Val ABCC8 p.Pro207Ser ABCC8 p.Asp212Asn ABCC8 p.Gln211Lys ABCC8 p.Leu225Pro Permanent Neonatal Diabetes Mellitus Transient Neonatal Diabetes Mellitus 1 5 10 15 20 25 30 35 39 N72S V86A V86G F132L F132V L135PP45L P207S E208K D209E Q211K L213R L225P T229I Y263D D209E D212I D212N T229I R306H V324M L438F L451P E382K R826W R1183W R1183Q A1185E E1327K R1314H M1290V R1380C R1380H R1380L G1401R V1523A V1523L H1024YC435R L582V I1425V Fig. 3 The location of missense mutations causing neonatal diabetes within the coding sequence of ABCC8. Login to comment 171 ABCC8 p.Phe132Leu The patient with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and the F132L mutation was not able to discontinue insulin [17]. Login to comment 175 ABCC8 p.Phe132Leu A second patient with the same mutation (F132L) had developmental delay but no epilepsy. Login to comment 176 ABCC8 p.Val86Ala ABCC8 p.Phe132Leu ABCC8 p.Leu135Pro ABCC8 p.Leu438Phe ABCC8 p.Arg306His ABCC8 p.Asp212Ile ABCC8 p.Asp209Glu ABCC8 p.Thr229Ile ABCC8 p.Leu582Val ABCC8 p.Tyr263Asp ABCC8 p.Val1523Ala ABCC8 p.Asn72Ser ABCC8 p.Cys435Arg ABCC8 p.Leu451Pro ABCC8 p.Glu382Lys ABCC8 p.Leu213Arg ABCC8 p.Val324Met ABCC8 p.Glu208Lys ABCC8 p.Pro207Ser ABCC8 p.Pro45Leu ABCC8 p.Gln211Lys ABCC8 p.Leu225Pro No neurological features were reported in R1183W/Q A1185E E1327K G1401R V1523A/L NBD1 NBD2 outside membrane inside P45L N72S F132L/V L135P P207S E208K D209E Q211K D212I/N L213R L225P T229I Y263D E382K V86A/G L438F C435R R1380C/H/L L451P R826W TMD0 TMD1 TMD2 R306H V324M L582V H1024Y I1425V R1314H M1290V Fig. 4 A schematic of the membrane topologies of SUR1 showing the location of the ABCC8 missense mutations causing neonatal diabetes. Login to comment 184 ABCC8 p.Phe132Val a third patient with a different mutation at the same residue (F132V). Login to comment 192 ABCC8 p.Asp212Ile Muscle weakness was identified in two cousins with the D212I mutation. Login to comment 194 ABCC8 p.Asp212Asn No muscle weakness was reported in either of their affected mothers or the three carriers of the D212N mutation [19]. Login to comment 197 ABCC8 p.Val86Ala ABCC8 p.Phe132Leu ABCC8 p.Leu135Pro ABCC8 p.Asp209Glu ABCC8 p.Leu213Arg ABCC8 p.Gln211Lys ABCC8 p.Leu225Pro Genotype-phenotype Correlation Most of the dominantly acting mutations located in exons 2-5 of the ABCC8 gene (V86A/G, F132L/V, L135P, D209E, Q211K, L213R and L225P) cause PNDM. Login to comment 198 ABCC8 p.Asp212Ile ABCC8 p.Asp212Asn The exceptions are D212I and D212N that result in a remitting/relapsing phenotype with permanent diabetes in later life. Login to comment 201 ABCC8 p.Asp209Glu The heterozygous mutation D209E has been reported as de novo in one proband (current age 6 years) with PNDM [14], and in a second family where the proband had TNDM but her mother was diagnosed with diabetes at 35 years of age [18]. Login to comment 203 ABCC8 p.Pro45Leu Both are compound heterozygotes for the P45L and G1401R mutations. Login to comment 224 ABCC8 p.Val86Ala ABCC8 p.Phe132Leu ABCC8 p.Asp212Ile Furthermore, different mutations at the same residue (V86A/G, F132L/V, D212I/N, R1183Q/W and R1380C/H/L) cause either PNDM (V86 and F132) or biphasic TNDM (D212, R1183 and R1380), suggesting a different pathological mechanism. Login to comment 227 ABCC8 p.Phe132Leu The cluster of neonatal diabetes causing mutations in the first five exons of the ABCC8 gene that encode these regions might cause diabetes by increasing the open stability of the channel through interaction with the Kir6.2 subunit as demonstrated for the F132L mutation [17]. Login to comment 234 ABCC8 p.Val1523Ala However, activating mutations in these NBD regions have now been reported (e.g. R826W, R1380C/H/L and V1523A/L) that could act to enhance the stimulatory effect of magnesium nucleotide binding or reduce the hydrolysis rate of Mg-ATP [16]. Login to comment 242 ABCC8 p.Thr229Ile We report the first patient with TNDM and a homozygous ABCC8 mutation (T229I). Login to comment 243 ABCC8 p.Thr229Ile ABCC8 p.Val1523Leu This mutation has previously been found in a child with PNDM who is a compound heterozygote for T229I and V1523L. Login to comment 244 ABCC8 p.Thr229Ile ABCC8 p.Thr229Ile ABCC8 p.Val1523Leu ABCC8 p.Val1523Leu Functional studies of heterozygous mutant channels suggested that V1523L has a greater effect on ATP sensitivity than T229I [14] and is consistent with the more severe PNDM phenotype caused by the T229I/V1523L genotype. Login to comment 247 ABCC8 p.Phe132Leu ABCC8 p.Thr229Ile ABCC8 p.Val1523Leu ABCC8 p.Pro207Ser ABCC8 p.Leu225Pro Functional data have only been published for 8/39 ABCC8 missense mutations to date (F132L [16]; I1425V and H1024Y [13]; mutations (P207S, T229I, A1185E and V1523L [14]; L225P [16]). Login to comment