ABCC8 p.Ala90Val
| Predicted by SNAP2: | C: N (82%), D: D (66%), E: D (59%), F: N (57%), G: N (87%), H: N (53%), I: N (72%), K: D (63%), L: N (66%), M: N (57%), N: D (59%), P: D (59%), Q: N (53%), R: D (59%), S: N (93%), T: N (72%), V: N (87%), W: D (63%), Y: D (53%), |
| Predicted by PROVEAN: | C: N, D: D, E: D, F: D, G: N, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: N, V: N, W: D, Y: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[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.
Comments [show]
None has been submitted yet.
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.
X
ABCC8 p.Ala90Val 17635943:7:71
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).
X
ABCC8 p.Ala90Val 17635943:56:45
status: NEWX
ABCC8 p.Ala90Val 17635943:56:94
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.
X
ABCC8 p.Ala90Val 17635943:79:89
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.
X
ABCC8 p.Ala90Val 17635943:88:65
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.
X
ABCC8 p.Ala90Val 17635943:98:1202
status: NEW159 The novel A90V and N1122D mutations are located in TMD0 and TMD2, respectively.
X
ABCC8 p.Ala90Val 17635943:159:10
status: NEW162 Thus, the functional consequence of the novel mutations A90V and N1122D is likely to overactivate beta-cell ATP-sensitive Kϩ channels.
X
ABCC8 p.Ala90Val 17635943:162:56
status: NEW[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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
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.
X
ABCC8 p.Ala90Val 20922570:85:308
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.
Comments [show]
None has been submitted yet.
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.
X
ABCC8 p.Ala90Val 18990670:204:28
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.
X
ABCC8 p.Ala90Val 18990670:207:28
status: NEW