ABCC8 p.Asp212Asn
| Predicted by SNAP2: | A: D (53%), C: D (53%), E: N (82%), F: D (53%), G: N (53%), H: D (53%), I: N (72%), K: D (53%), L: D (53%), M: N (57%), N: N (57%), P: D (63%), Q: N (53%), R: D (53%), S: N (61%), T: N (61%), V: D (53%), W: D (63%), Y: N (53%), |
| Predicted by PROVEAN: | A: D, C: D, E: N, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] Mutations in the ABCC8 gene encoding the SUR1 subu... Diabetes Obes Metab. 2007 Nov;9 Suppl 2:28-39. 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., [PMID:17919176]
Abstract [show]
AIM: Mutations in the ABCC8 gene encoding the SUR1 subunit of the pancreatic ATP-sensitive potassium channel cause permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). We reviewed the existing literature, extended the number of cases and explored genotype-phenotype correlations. METHODS: Mutations were identified by sequencing in patients diagnosed with diabetes before 6 months without a KCNJ11 mutation. 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. Both dominant and recessive mutations were observed with recessive inheritance more common in PNDM than TNDM (9 vs. 1; p < 0.01). The remainder of the PNDM probands (n = 12) had de novo mutations. Seventeen of twenty-five children with TNDM inherited their heterozygous mutation from a parent. Nine of these parents had permanent diabetes (median age at diagnosis: 27.5 years, range: 13-35 years). Recurrent mutations of residues R1183 and R1380 were found only in TNDM probands and dominant mutations causing PNDM clustered within exons 2-5. CONCLUSIONS: ABCC8 mutations cause PNDM, TNDM or permanent diabetes diagnosed outside the neonatal period. There is some evidence that the location of the mutation is correlated with the clinical phenotype.
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No. Sentence Comment
161 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.
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ABCC8 p.Asp212Asn 17919176:161:270
status: NEW163 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.
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ABCC8 p.Asp212Asn 17919176:163:196
status: NEW194 No muscle weakness was reported in either of their affected mothers or the three carriers of the D212N mutation [19].
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ABCC8 p.Asp212Asn 17919176:194:97
status: NEW198 The exceptions are D212I and D212N that result in a remitting/relapsing phenotype with permanent diabetes in later life.
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ABCC8 p.Asp212Asn 17919176:198:29
status: NEW[hide] Review. SUR1: a unique ATP-binding cassette protei... Philos Trans R Soc Lond B Biol Sci. 2009 Jan 27;364(1514):257-67. Aittoniemi J, Fotinou C, Craig TJ, de Wet H, Proks P, Ashcroft FM
Review. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator.
Philos Trans R Soc Lond B Biol Sci. 2009 Jan 27;364(1514):257-67., [PMID:18990670]
Abstract [show]
SUR1 is an ATP-binding cassette (ABC) transporter with a novel function. In contrast to other ABC proteins, it serves as the regulatory subunit of an ion channel. The ATP-sensitive (KATP) channel is an octameric complex of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits, and it links cell metabolism to electrical activity in many cell types. ATPase activity at the nucleotide-binding domains of SUR results in an increase in KATP channel open probability. Conversely, ATP binding to Kir6.2 closes the channel. Metabolic regulation is achieved by the balance between these two opposing effects. Precisely how SUR1 talks to Kir6.2 remains unclear, but recent studies have identified some residues and domains that are involved in both physical and functional interactions between the two proteins. The importance of these interactions is exemplified by the fact that impaired regulation of Kir6.2 by SUR1 results in human disease, with loss-of-function SUR1 mutations causing congenital hyperinsulinism and gain-of-function SUR1 mutations leading to neonatal diabetes. This paper reviews recent data on the regulation of Kir6.2 by SUR1 and considers the molecular mechanisms by which SUR1 mutations produce disease.
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No. Sentence Comment
185 Such naturally occurring mutations TNDM PNDM DEND TNDM PNDM DEND iDEND WT P206L D212N P45L N72S P207S E208K+Y263D D212I T229I A1185E V1522L+Y229I F132L 0 0.05 0.10 0.15 fractionofcurrentremaining in3mMMgATP(a) (b) (i) (ii) Figure 4.
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ABCC8 p.Asp212Asn 18990670:185:80
status: NEW188 Such naturally occurring mutations TNDM PNDM DEND TNDM PNDM DEND iDEND WT P206L D212N P45L N72S P207S E208K+Y263D D212I T229I A1185E V1522L+Y229I F132L 0 0.05 0.10 0.15 fraction of current remaining in 3 mM MgATP (a) (b) (i) (ii) Figure 4.
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ABCC8 p.Asp212Asn 18990670:188:80
status: NEW[hide] Mutations in ATP-sensitive K+ channel genes cause ... Diabetes. 2007 Jul;56(7):1930-7. Epub 2007 Apr 19. Flanagan SE, Patch AM, Mackay DJ, Edghill EL, Gloyn AL, Robinson D, Shield JP, Temple K, Ellard S, Hattersley AT
Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood.
Diabetes. 2007 Jul;56(7):1930-7. Epub 2007 Apr 19., [PMID:17446535]
Abstract [show]
Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early childhood. For approximately 50% of patients, their diabetes will relapse in later life. The majority of cases result from anomalies of the imprinted region on chromosome 6q24, and 14 patients with ATP-sensitive K+ channel (K(ATP) channel) gene mutations have been reported. We determined the 6q24 status in 97 patients with TNDM. In patients in whom no abnormality was identified, the KCNJ11 gene and/or ABCC8 gene, which encode the Kir6.2 and SUR1 subunits of the pancreatic beta-cell K(ATP) channel, were sequenced. K(ATP) channel mutations were found in 25 of 97 (26%) TNDM probands (12 KCNJ11 and 13 ABCC8), while 69 of 97 (71%) had chromosome 6q24 abnormalities. The phenotype associated with KCNJ11 and ABCC8 mutations was similar but markedly different from 6q24 patients who had a lower birth weight and who were diagnosed and remitted earlier (all P < 0.001). K(ATP) channel mutations were identified in 26 additional family members, 17 of whom had diabetes. Of 42 diabetic patients, 91% diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (P < 0.0001). K(ATP) channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype that includes biphasic diabetes that can be treated with sulfonylureas. Remitting neonatal diabetes was observed in two of three mutation carriers, and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes.
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No. Sentence Comment
71 Ten different ABCC8 gene mutations were identified in 13 probands: D209E (c.627CϾA), D212N (c.634GϾA), D212I (c.634 GϾA 635AϾT), V324M (c.970GϾA), L451P (c.1352TϾC), R826W (c.2476CϾT), R1183W (c.3547CϾT), R1183Q (c.3548GϾA), R1380C (c.4138CϾT), and R1380H (c.4139GϾA).
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ABCC8 p.Asp212Asn 17446535:71:91
status: NEW138 TABLE 3 Comparison of clinical and biochemical characteristics of patients with a KATP channel mutation diagnosed before 6 months of age with patients whose diabetes was not diagnosed before age 6 months and the number of each mutation identified within each group Characteristic Mutation carriers diagnosed with diabetes within 6 months Mutation carriers who did not have diabetes diagnosed within the first 6 months P value n (% male) 35 (51) 16 (44) 0.75 Probands (n) 25 0 Age when entering study (years) 6 (0.8-43) 42 (5-56) - Ever diagnosed with diabetes (n) 35 7 1*10-6 Age at diagnosis (weeks) 4 (0-17) 1196 (260 to Ͼ2496) 3.7*10-5 Diabetes remitted (n) 32 0/7 3.7*10-10 Age at remission (weeks) 35 (2-208) - - Diabetes relapsed (n) 7 - - Age at relapse (years) 13 (3-25.5) - - Birth weight (g) 2,695 (1,360-3,570) 2,810 (907-3,090) 0.9 Gestation (weeks) 39 (30-42) 38 (34-40) 0.74 Centile birth weight 18 (Ͻ1st to 89th) 15 (Ͻ1st to 79th) 0.94 KCNJ11 mutations R34C 1 2 G53R 2 0 G53S 2 1 E179A 1 0 I182V 1 0 E227K 4 2 E229K 5 3 R365H 1 1 ABCC8 mutations D209E 1 1 D212N 2 1 D212I 4 0 V324M 1 1 L451P 2 1 R826W 1 0 R1183W 4 2 R1183Q 1 0 R1380C 1 0 R1380H 1 1 Data are median (range), unless otherwise indicated.
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ABCC8 p.Asp212Asn 17446535:138:1089
status: NEW171 There are a cluster of mutations (D209E, D212N, and D212I) in the intracellular region that links the transmembrane domain with the gatekeeper module (8).
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ABCC8 p.Asp212Asn 17446535:171:41
status: NEW72 Ten different ABCC8 gene mutations were identified in 13 probands: D209E (c.627Cb0e;A), D212N (c.634Gb0e;A), D212I (c.634 Gb0e;A 635Ab0e;T), V324M (c.970Gb0e;A), L451P (c.1352Tb0e;C), R826W (c.2476Cb0e;T), R1183W (c.3547Cb0e;T), R1183Q (c.3548Gb0e;A), R1380C (c.4138Cb0e;T), and R1380H (c.4139Gb0e;A).
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ABCC8 p.Asp212Asn 17446535:72:91
status: NEW139 TABLE 3 Comparison of clinical and biochemical characteristics of patients with a KATP channel mutation diagnosed before 6 months of age with patients whose diabetes was not diagnosed before age 6 months and the number of each mutation identified within each group Characteristic Mutation carriers diagnosed with diabetes within 6 months Mutation carriers who did not have diabetes diagnosed within the first 6 months P value n (% male) 35 (51) 16 (44) 0.75 Probands (n) 25 0 Age when entering study (years) 6 (0.8-43) 42 (5-56) - Ever diagnosed with diabetes (n) 35 7 1*10afa;6 Age at diagnosis (weeks) 4 (0-17) 1196 (260 to b0e;2496) 3.7*10afa;5 Diabetes remitted (n) 32 0/7 3.7*10afa;10 Age at remission (weeks) 35 (2-208) - - Diabetes relapsed (n) 7 - - Age at relapse (years) 13 (3-25.5) - - Birth weight (g) 2,695 (1,360-3,570) 2,810 (907-3,090) 0.9 Gestation (weeks) 39 (30-42) 38 (34-40) 0.74 Centile birth weight 18 (b0d;1st to 89th) 15 (b0d;1st to 79th) 0.94 KCNJ11 mutations R34C 1 2 G53R 2 0 G53S 2 1 E179A 1 0 I182V 1 0 E227K 4 2 E229K 5 3 R365H 1 1 ABCC8 mutations D209E 1 1 D212N 2 1 D212I 4 0 V324M 1 1 L451P 2 1 R826W 1 0 R1183W 4 2 R1183Q 1 0 R1380C 1 0 R1380H 1 1 Data are median (range), unless otherwise indicated.
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ABCC8 p.Asp212Asn 17446535:139:1107
status: NEW172 There are a cluster of mutations (D209E, D212N, and D212I) in the intracellular region that links the transmembrane domain with the gatekeeper module (8).
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ABCC8 p.Asp212Asn 17446535:172:41
status: NEW