ABCC8 p.Asn1122Asp
| Predicted by SNAP2: | A: D (75%), C: D (75%), D: D (85%), E: D (85%), F: D (85%), G: D (80%), H: D (75%), I: D (80%), K: D (85%), L: D (85%), M: D (80%), P: D (85%), Q: D (71%), R: D (85%), S: D (59%), T: D (66%), V: D (80%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Molecular basis of neonatal diabetes in Japanese p... J Clin Endocrinol Metab. 2007 Oct;92(10):3979-85. Epub 2007 Jul 17. Suzuki S, Makita Y, Mukai T, Matsuo K, Ueda O, Fujieda K
Molecular basis of neonatal diabetes in Japanese patients.
J Clin Endocrinol Metab. 2007 Oct;92(10):3979-85. Epub 2007 Jul 17., [PMID:17635943]
Abstract [show]
CONTEXT: Neonatal diabetes mellitus (NDM) is classified clinically into a transient form (TNDM), in which insulin secretion recovers within several months, and a permanent form (PNDM), requiring lifelong medication. However, these conditions are genetically heterogeneous. OBJECTIVE: Our objective was to evaluate the contribution of the responsible gene and delineate their clinical characteristics. PATIENTS AND METHODS: The chromosome 6q24 abnormality and KCNJ11 and ABCC8 mutations were analyzed in 31 Japanese patients (16 with TNDM and 15 with PNDM). Moreover, FOXP3 and IPF1 mutations were analyzed in a patient with immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome and with pancreatic agenesis, respectively. RESULTS: A molecular basis for NDM was found in 23 patients: 6q24 in eleven, KCNJ11 in nine, ABCC8 in two, and FOXP3 in one. All the patients with the 6q24 abnormality and two patients with the KCNJ11 mutation proved to be TNDM. Five mutations were novel: two (p.A174G and p.R50G) [corrected] in KCNJ11, two (p.A90V and p.N1122D) in ABCC8, and one (p.P367L) in FOXP3. Comparing the 6q24 abnormality and KCNJ11 mutation, there were some significant clinical differences: the earlier onset of diabetes, the lower frequency of diabetic ketoacidosis at onset, and the higher proportion of the patients with macroglossia at initial presentation in the patients with 6q24 abnormality. In contrast, two patients with the KCNJ11 mutations manifested epilepsy and developmental delay. CONCLUSIONS: Both the 6q24 abnormality and KCNJ11 mutation are major causes of NDM in Japanese patients. Clinical differences between them could provide important insight into the decision of which gene to analyze in affected patients first.
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No. Sentence Comment
7 Five mutations were novel: two (p.A174G and p.C166Y) in KCNJ11, two (p.A90V and p.N1122D) in ABCC8, and one (p.P367L) in FOXP3.
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ABCC8 p.Asn1122Asp 17635943:7:82
status: NEW56 The novel mutations were the substitution of alanine by valine at codon 90 (c.269CϾT, p.A90V) and the substitution of asparagine by aspartate at codon 1122 (c.3364AϾG, p.N1122D).
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ABCC8 p.Asn1122Asp 17635943:56:124
status: NEWX
ABCC8 p.Asn1122Asp 17635943:56:182
status: NEW79 They exhibited hyperglycemia, leading to fever and dehydration in the patient with the A90V mutation and severe DKA, resulting in seizure in the patient with the N1122D mutation.
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ABCC8 p.Asn1122Asp 17635943:79:164
status: NEW88 The patients with R50G, C166Y, R201C, or R201H in the KCNJ11 and A90V mutations or N1122D in the ABCC8 mutation have been treated with insulin since diagnosis of diabetes.
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ABCC8 p.Asn1122Asp 17635943:88:83
status: NEW98 Sex Year of birth Age at last visit (yr) Diabetes form Genetic defect Age at onset of diabetes (d) Age at remission (d) Remark 1 M 2001 0.7 TNDM pUPD(6) 10 161 Macroglossia at onset 2 M 2002 2.8 TNDM pUPD(6) 9 104 Macroglossia at onset 3 M 2005 0.6 TNDM pUPD(6) 4 62 4 F 2002 0.3 TNDM pUPD(6) 11 62 Macroglossia at onset 5 F 2003 2.0 TNDM pUPD(6) 0 91 Extremely premature baby 6 F 2005 0.4 TNDM pUPD(6) 8 39 7 F 2000 5.4 TNDM pUPD(6) 1 26 Prominent forehead 8 M 2004 0.7 TNDM 6q24 duplication 6 16 9 M 2002 2.5 TNDM 6q24 duplication 2 173 Macroglossia at onset 10 M 2004 0.9 TNDM 6q24 duplication 8 35 Macroglossia at onset 11 F 1994 11.2 TNDM 6q24 duplication 6 246 Recurrence at 10 yr of age (38) 12 M 2003 1.3 TNDM KCNJ11 (p.R50Q) 9 307 13 M 1986 14.6 TNDM KCNJ11 (p.A174G) 17 307 Recurrence at 13 yr of age 14 M 2004 2.0 PNDM KCNJ11 (p.R201H) 33 15 F 2004 0.5 PNDMa KCNJ11 (p.R201H) 54 16 M 2004 2.0 PNDM KCNJ11 (p.R201H) 42 17 M 2006 0.3 PNDMa KCNJ11 (p.R201H) 54 18 F 2000 5.0 PNDM KCNJ11 (p.R201C) 49 19 M 1997 8.3 PNDM KCNJ11 (p.R50G) 115 DEND syndrome, arthroglyposis 20 F 2003 3.1 PNDM KCNJ11 (p.C166Y) 98 DEND syndrome, arthroglyposis, prominent forehead, ptosis 21 M 2004 1.7 PNDM ABCC8 (p.A90V) 40 22 M 2006 0.3 PNDMa ABCC8 (p.N1122D) 50 23 M 2001 0.3 PNDM FOXP3 (p.P367 liter) 8 Died at 4 months of age 24 M 2000 3.6 TNDM Unknown 10 27 Extremely premature baby 25 M 2001 0.2 TNDM Unknown 11 25 Extremely premature baby 26 M 2005 0.2 TNDM Unknown 13 60 Macroglossia at onset 27 M 2003 1.9 PNDM Unknown (no IPF1 mutation) 9 Pancreatic agenesis 28 M 2002 3.4 PNDM Unknownb 42 29 M 2002 1.2 PNDM Unknown 18 Congenital deafness, cataract, mental retardation, liver dysfunction 30 M 1991 13.9 PNDM Unknown 55 Severe developmental delay 31 F 2002 3.0 PNDM Unknown 93 Congenital cataract, severe developmental delay F, Female; M, male.
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ABCC8 p.Asn1122Asp 17635943:98:1240
status: NEW126 *, Classification of diabetes of two patients with R201H in the KCNJ11 mutation, and the patient with N1122D in the ABCC8 mutation may remain undetermined because of the short follow-up period.
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ABCC8 p.Asn1122Asp 17635943:126:102
status: NEW159 The novel A90V and N1122D mutations are located in TMD0 and TMD2, respectively.
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ABCC8 p.Asn1122Asp 17635943:159:19
status: NEW162 Thus, the functional consequence of the novel mutations A90V and N1122D is likely to overactivate beta-cell ATP-sensitive Kϩ channels.
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ABCC8 p.Asn1122Asp 17635943:162:65
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
204 (a) (b) P45L N72S F132L NH2 A90V V86G COOHL135P exoplasmic cytoplasmic Walker A Walker A linker Walker B linker Walker B V324M E382K C435R L438F L582V R826W H1023Y N1122D R1183Q A1185E R1314H E1327K R1380 L I1425V V1524 L P207S E208K Q211K D212I/N L225P T229I Y263D A269D R306H D209E L213R TMD0 TMD1 TMD2 NBD1 NBD2 CL3 linker site 1 site 2 NBD1 NBD2 R826W R1380 L E1327K I1425V V1524 L Figure 5.
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ABCC8 p.Asn1122Asp 18990670:204:164
status: NEW207 (a) (b) P45L N72S F132L NH2 A90V V86G COOH L135P exoplasmic cytoplasmic Walker A Walker A linker Walker B linker Walker B V324M E382K C435R L438F L582V R826W H1023Y N1122D R1183Q A1185E R1314H E1327K R1380 L I1425V V1524 L P207S E208K Q211K D212I/N L225P T229I Y263D A269D R306H D209E L213R TMD0 TMD1 TMD2 NBD1 NBD2 CL3 linker site 1 site 2 NBD1 NBD2 R826W R1380 L E1327K I1425V V1524 L Figure 5.
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ABCC8 p.Asn1122Asp 18990670:207:165
status: NEW