ABCMdb

ABCC8 p.Leu451Pro

Predicted by SNAP2:	A: N (57%), C: N (66%), D: D (75%), E: D (71%), F: N (87%), G: D (66%), H: D (63%), I: N (93%), K: D (71%), M: N (78%), N: D (59%), P: D (71%), Q: D (63%), R: D (71%), S: N (57%), T: D (53%), V: N (72%), W: D (66%), Y: N (61%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, 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. Login to comment
163 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
176 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

[hide] Permanent neonatal diabetes due to activating muta... Rev Endocr Metab Disord. 2010 Sep;11(3):193-8. Edghill EL, Flanagan SE, Ellard S
Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11.
Rev Endocr Metab Disord. 2010 Sep;11(3):193-8., [PMID:20922570]

Abstract [show]
The ATP-sensitive potassium (K(ATP)) channel is composed of two subunits SUR1 and Kir6.2. The channel is key for glucose stimulated insulin release from the pancreatic beta cell. Activating mutations have been identified in the genes encoding these subunits, ABCC8 and KCNJ11, and account for approximately 40% of permanent neonatal diabetes cases. The majority of patients with a K(ATP) mutation present with isolated diabetes however some have presented with the Developmental delay, Epilepsy and Neonatal Diabetes syndrome. This review focuses on mutations in the K(ATP) channel which result in permanent neonatal diabetes, we review the clinical and functional effects as well as the implications for treatment.

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85 One of the most notable R1183W/Q A1185E E1327K G1401R V1523A/L V1524M R1531A NBD1 NBD2 outside membrane inside P45L N72S F132L/V L135P P207S E208K D209E Q211K D212I/N L213R L225P T229I Y263D A269D/N E382K V86A/G R1380C/H/L C435R L438F M1290V L451P R826W R1314H TMD0 TMD1 TMD2 R306H V324M L582V H1024Y I1425V A90V Y356C R521Q N1123D R1153G T1043TfsX74 Fig. 3 Schematic representation of 50 ABCC8 mutations which cause neonatal diabetes. Login to comment

[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). Login to comment
138 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. Login to comment
72 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). Login to comment
139 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. Login to comment

[hide] Incidence of neonatal diabetes in Austria-calculat... Pediatr Diabetes. 2010 Feb;11(1):18-23. Epub 2009 Jun 3. Wiedemann B, Schober E, Waldhoer T, Koehle J, Flanagan SE, Mackay DJ, Steichen E, Meraner D, Zimmerhackl LB, Hattersley AT, Ellard S, Hofer S
Incidence of neonatal diabetes in Austria-calculation based on the Austrian Diabetes Register.
Pediatr Diabetes. 2010 Feb;11(1):18-23. Epub 2009 Jun 3., [PMID:19496964]

Abstract [show]
BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare monogenic form of diabetes which is diagnosed in the first 6 months of life. Several studies in the last few years provide information on genetic causes for NDM. OBJECTIVE: The aim of this study was to identify all patients with diabetes in the first 6 months of life through the Austrian Diabetes Register, which is available since 1989. A retrospective data analyses was performed to calculate the current incidence of NDM. SUBJECTS AND METHODS: Ten patients were registered with diabetes onset within the first 6 months of life in the Austrian Diabetes Register. Evaluation of detailed clinical data was performed by sending a questionnaire to all diabetes centers. RESULTS: Ten patients from nine different families with NDM were diagnosed in Austria from 1989 until September 2007. Seven patients (one male, six females) had transient NDM (TNDM), three (two males, one female) showed a permanent course [permanent neonatal diabetes mellitus (PNDM)]. One had immunodeficiency, polyendocrinopathy and enteropathy X-linked (IPEX) syndrome and another showed aplasia of the pancreas; no genetic etiology was found in the third case. In three out of seven patients with a transient course of NDM a genetic diagnosis was possible. Two female siblings had activating point mutations in the ABCC8 gene, although one patient had paternal uniparental isodisomy of chromosome 6q24. One patient's family did not consent to genetic testing. CONCLUSIONS: The incidence of NDM in Austria is 1/160 949, with an incidence of 1/ 536 499 for PNDM and 1/229 928 for TNDM.

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54 A paternally inherited ABCC8 missense mutation, L451P (c.1352T > C; p.Leu451Pro), was found in two female siblings (patient 5 and 6) who have been reported previously (5). Login to comment