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A novel mutation of KCNJ11 gene in a patient with permanent neonatal diabetes mellitus
diabetes research and clinical practice 104 (2014) e29–e32
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
A novel mutation of KCNJ11 gene in a patient with permanent neonatal diabetes mellitus Wei-Lun Chang a, Chun-Jui Huang a, Tsun-Hsiang Lei a, Dau-Ming Niu b, Chih-Yang Chiu c, Tjin-Shing Jap a,* a
Division of Endocrinology and Metabolism, Department of Medicine, Taipei, Taiwan, ROC Section of Molecular Genetics, Department of Pediatrics, Taipei, Taiwan, ROC c Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC b
article info
abstract
Article history:
A 4-month-old male baby was diagnosed with Permanent Neonatal Diabetes Mellitus. We
Received 16 April 2013
identified a novel missense heterogeneous mutation in the KCNJ11 gene at codon 167
Received in revised form
(aTC ! tTC) in a region that corresponds to a predicted intracellular gate of the ATP-
7 August 2013
sensitive potassium channel. # 2014 Elsevier Ireland Ltd. All rights reserved.
Accepted 28 December 2013 Available online 8 January 2014 Keywords: Permanent neonatal diabetes mellitus KCNJ11 mutation Sulfonylurea Chinese
1.
Introduction
Permanent neonatal diabetes mellitus (PNDM) is rare and defined by the early onset of hyperglycemia before six months of age. The incidence of PNDM is around 1 in 260,000–500,000 births [1–3]. Mutations in several genes have been found to be associated with disease development, including the potassium channel, inwardly rectifying, subfamily J, member 11, Kir6.2 (KCNJ11) [4,5], Glucokinase (GCK) [6], insulin promoter factor-1 (IPF1) [7] and the ATP-binding cassette, sub-family C, member 8 gene (ABCC8) [8]. Mutations in the KCNJ11 gene account for more than 50% of all PNDM cases [9,10] and may be responsive to sulfonylurea [5]. More than 20 activating mutations of the KCNJ11 gene have been found but a great
majority of these cases were in Caucasian [11]. Relatively small numbers of PNDM in Chinese have been reported [12–16]. KCNJ11 mutations have been identified among them but none was novel [12–15].
2.
Materials and methods
2.1.
Case report
The male baby is the first child of non consanguineous Han Chinese parents. His mother was 32 years old and had gestational diabetes under diet control. At four months of age, he developed focal seizure and hyperglycemia without ketoacidosis. The brain magnetic resonance imaging (MRI)
* Corresponding author. Tel.: +886 2 28757516/+886 2 28757158; fax: +886 2 28724982. E-mail address: [email protected] (T.-S. Jap). 0168-8227/$ – see front matter # 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.diabres.2013.12.058
e30
diabetes research and clinical practice 104 (2014) e29–e32
Fig. 1 – T1-weighted (left) and T2-weighted (right) MRI of brain of the patient. T2-weighted MRI reveal hyperintense lesion over left fronto-parietal area (arrow) in favor of previous intracranial hemorrhage.
demonstrated a hyper-intense lesion over the left frontoparietal area consistent with previous intracranial hemorrhage (Fig. 1). Laboratory results showed a plasma glucose of 17.3 mmol/L and HbA1c of 11% (97 mmol/mol). Insulin therapy was prescribed for hyperglycemia. The C-peptide concentrations before and 6 min after 1 mg intravenous glucagon infusion, were 0.18 nmol/L and 0.77 nmol/L, respectively. Therefore, we started Glimepiride (Sanofi-Aventis) at 0.05 mg/ kg/day and gradually tapered the insulin dosage. The Glimepiride dosage reached 0.09 mg/kg/day when insulin therapy was discontinued completely and follow-up HbA1c level was 6.6% (49 mmol/mol). Since PNDM was diagnosed within the first six months of life and responsive to oral sulfonylurea, we sequenced his KCNJ11 gene. Apart from Tourette syndrome and attention deficithyperactivity disorder, he did not have other cognitive, language or motor function impairment. He had been receiving Glimepiride treatment for almost 11 years and tolerates it well.
3.
Result and discussion
The index patient had a heterozygous missense mutation at codon 167 (c499A>T) (Fig. 2A) that resulted in a substitution of isoleucine by phenylalanine. We used restriction analysis with restriction enzyme MslI to confirm the presence of mutations in the KCNJ11 gene (Fig. 2B). This is a de novo mutation since the patient’s parents do not have this mutation. It is consistent with previous report that >90% of KCNJ11 gene-related PNDM arise spontaneously [12]. The human KCNJ11 gene encodes a membrane protein Kir6.2. The ATP-sensitive potassium channel (KATP) of the pancreatic beta cell is formed by four Kir6.2 subunits and four sulfonylurea subunits in an octomeric structure [4]. The four Kir6.2 subunits form the pore of ATP-sensitive potassium channel. Residues L164 to F168 construct a hydrophobic girdle and are the narrowest part of the channel. This region is thought to be the intracellular gate and mutation of
Fig. 2 – (A) Gene sequencing figure of the patient with heterozygous c.499A>T mutation. (B) Restriction analysis of the amplification products of the KCNJ11 gene with restriction enzyme MslI at 37 8C. PCR product is 720 bps. Normal allele are 273, 315, 132 bps and mutant allele 273, 447 bps, respectively.
individual residues affects the opening frequency and duration of the channel [17]. The mutation Kir6.2-I167F we identified lies within this region. Although a functional study was not performed in Kir6.2I167F, it has been carried out in a different mutation at the same codon, the Kir6.2-I167L (c.499A>C). Shimomura et al. demonstrated that both heterozygous and homomeric mutants of I167L reduced the ATP sensitivity and increased the current of the KATP channel. This effect is caused by an increasing intrinsic open probability of the KATP channel, which prevents insulin secretion from pancreatic beta cell and results in neonatal diabetes [18]. The change of amino acid in
diabetes research and clinical practice 104 (2014) e29–e32
e31
Fig. 3 – The spectrum of mutations causing PNDM within the sequence of Kir6.2 in Han Chinese. TM1 denotes first transmembrane domain and TM2, second transmembrane domain; N,N-terminal; C,C-terminal.
I167L is between aliphatic amino acids, but the I167F we identified results in a more radical change from aliphatic to aromatic amino acid. To the best of our knowledge, four reports of KCNJ11 mutation in neonatal diabetes of Chinese have been reported in the literature (Fig. 3). These patients were treated with insulin at first and all shifted to sulfonylurea successfully. One R201C [15], one R201H [12] and two V59M [13,14] mutations were identified among them and all of these mutations had been reported previously [11]. By contrast, an 18-year-old Korean patient with an R201H mutation who did not respond to sulfonylurea treatment has been reported recently. The reason for unsuccessful switch to sulfonylurea may be the long disease process resulting in pancreatic beta-cell function failure [19]. The Kir6.2-I167F is the first novel mutation reported in ethnic Chinese. In 2012, Li et al. reviewed the clinical manifestation of 40 neonatal diabetes patients in the available Chinese literature. Among them, two patients had an intracranial hemorrhage, similar to our patient. One patient had epilepsy and 19 patients had intrauterine growth restriction. Genetic studies were carried out in three patients only [13]. Four patients received sulfonylurea and insulin (including the 3 patients who had genetic studies), 24 patients received insulin treatment only and the treatment modalities of the remaining patients were not mentioned [20]. Early genetic analysis in neonatal diabetes may change life quality dramatically. Once a mutation in the KCNJ11 or ABCC8 gene is confirmed, insulin therapy may be switched to oral sulfonylurea.
4.
Conclusion
In summary, we identified a novel Kir6.2-I167F mutation causing PNDM in a Han Chinese, which is also the first reported case of PNDM with KCNJ11 mutation in Taiwan. Successful treatment with oral sulfonylurea in our patient reemphasized the importance of early genetic analysis in neonatal diabetes.
Conflict of interest The authors declare that there are no conflicts of interest.
Acknowledgments This study was supported by grants from Medical ResearchVGH and National Science Council-NSC 96-2314-B-075-018MY3, Taiwan/ROC.
references
[1] Shield JP, Gardner RJ, Wadsworth EJ, Whiteford ML, James RS, Robinson DO, et al. Aetiopathology and genetic basis of neonatal diabetes. Arch Dis Child 1997;76:F39–42. [2] von Mu¨hlendahl KE, Herkenhoff H. Long-term course of neonatal diabetes. N Engl J Med 1995;333:704–8. [3] Slingerland AS, Shields BM, Flanagan SE, Bruining GJ, Noordam K, Gach A, et al. Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live births. Diabetologia 2009;52:1683–5. [4] Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004;350:1838–49. [5] Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, et al. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 2004;53:2713–8. [6] Njølstad PR, Søvik O, Cuesta-Mun˜oz A, Bjørkhaug L, Massa O, Barbetti F, et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 2001;344:1588–92. [7] Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997;15:106–10. [8] Babenko AP, Polak M, Cave´ H, Busiah K, Czernichow P, Scharfmann R, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006;355:456–66. [9] Vaxillaire M, Populaire C, Busiah K, Cave´ H, Gloyn AL, Hattersley AT, et al. Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes 2004;53:2719–22. [10] Massa O, Iafusco D, D‘Amato E, Gloyn AL, Hattersley AT, Pasquino B, et al. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat 2005;25:22–7. [11] Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 2005; 54:2503–13. [12] Xiao X, Wang T, Li W, Song H, Gong C, Diao C, et al. Transfer from insulin to sulfonylurea treatment in a Chinese patient with permanent neonatal diabetes mellitus due to a KCNJ11 R201H mutation. Horm Metab Res 2009;41:580–2. [13] Sang Y, Ni G, Gu Y, Liu M. KCNJ11 gene mutation in 3 cases with neonatal diabetes mellitus. Chin J Endocrinol Metab 2010;26:682–3. [14] Sang Y, Ni G, Gu Y, Liu M. AV59M KCNJ11 gene mutation leading to intermediate DEND syndrome in a Chinese child. J Pediatr Endocrinol Metab 2011;24:763–6.
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diabetes research and clinical practice 104 (2014) e29–e32
[15] Wang SY, Zhang LJ, He ZQ, Tian Q, Li XD. Neonatal diabetes mellitus caused by KCNJ11 mutation: a case report. CJCP 2012;14:73–5. [16] Mak CM, Lee CY, Lam CW, Siu WK, Hung VC, Chan AY. Personalized medicine switching from insulin to sulfonylurea in permanent neonatal diabetes mellitus dictated by a novel activating ABCC8 mutation. Diagn Mol Pathol 2012;21:56–9. [17] Haider S, Antcliff JF, Proks P, Sansom MS, Ashcroft FM. Focus on Kir6.2: a key component of the ATP-sensitive potassium channel. J Mol Cell Cardiol 2005;38:927–36.
[18] Shimomura K, Ho¨rster F, de Wet H, Flanagan SE, Ellard S, Hattersley AT, et al. A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain. Neurology 2007;69:1342–9. [19] Heo JW, Kim SW, Cho EH. Unsuccessful switch from insulin to sulfonylurea therapy in permanent neonatal diabetes mellitus due to an R201H mutation in the KCNJ11 gene: a case report. Diabetes Res Clin Pract 2013;100(1):e1–2. [20] Li YH, Yuan TM, Yu HM. Neonatal diabetes mellitus in China: a case report and review of the Chinese literature. Clin Pediatr (Phila) 2012;51:366–73.
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
A novel mutation of KCNJ11 gene in a patient with permanent neonatal diabetes mellitus Wei-Lun Chang a, Chun-Jui Huang a, Tsun-Hsiang Lei a, Dau-Ming Niu b, Chih-Yang Chiu c, Tjin-Shing Jap a,* a
Division of Endocrinology and Metabolism, Department of Medicine, Taipei, Taiwan, ROC Section of Molecular Genetics, Department of Pediatrics, Taipei, Taiwan, ROC c Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC b
article info
abstract
Article history:
A 4-month-old male baby was diagnosed with Permanent Neonatal Diabetes Mellitus. We
Received 16 April 2013
identified a novel missense heterogeneous mutation in the KCNJ11 gene at codon 167
Received in revised form
(aTC ! tTC) in a region that corresponds to a predicted intracellular gate of the ATP-
7 August 2013
sensitive potassium channel. # 2014 Elsevier Ireland Ltd. All rights reserved.
Accepted 28 December 2013 Available online 8 January 2014 Keywords: Permanent neonatal diabetes mellitus KCNJ11 mutation Sulfonylurea Chinese
1.
Introduction
Permanent neonatal diabetes mellitus (PNDM) is rare and defined by the early onset of hyperglycemia before six months of age. The incidence of PNDM is around 1 in 260,000–500,000 births [1–3]. Mutations in several genes have been found to be associated with disease development, including the potassium channel, inwardly rectifying, subfamily J, member 11, Kir6.2 (KCNJ11) [4,5], Glucokinase (GCK) [6], insulin promoter factor-1 (IPF1) [7] and the ATP-binding cassette, sub-family C, member 8 gene (ABCC8) [8]. Mutations in the KCNJ11 gene account for more than 50% of all PNDM cases [9,10] and may be responsive to sulfonylurea [5]. More than 20 activating mutations of the KCNJ11 gene have been found but a great
majority of these cases were in Caucasian [11]. Relatively small numbers of PNDM in Chinese have been reported [12–16]. KCNJ11 mutations have been identified among them but none was novel [12–15].
2.
Materials and methods
2.1.
Case report
The male baby is the first child of non consanguineous Han Chinese parents. His mother was 32 years old and had gestational diabetes under diet control. At four months of age, he developed focal seizure and hyperglycemia without ketoacidosis. The brain magnetic resonance imaging (MRI)
* Corresponding author. Tel.: +886 2 28757516/+886 2 28757158; fax: +886 2 28724982. E-mail address: [email protected] (T.-S. Jap). 0168-8227/$ – see front matter # 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.diabres.2013.12.058
e30
diabetes research and clinical practice 104 (2014) e29–e32
Fig. 1 – T1-weighted (left) and T2-weighted (right) MRI of brain of the patient. T2-weighted MRI reveal hyperintense lesion over left fronto-parietal area (arrow) in favor of previous intracranial hemorrhage.
demonstrated a hyper-intense lesion over the left frontoparietal area consistent with previous intracranial hemorrhage (Fig. 1). Laboratory results showed a plasma glucose of 17.3 mmol/L and HbA1c of 11% (97 mmol/mol). Insulin therapy was prescribed for hyperglycemia. The C-peptide concentrations before and 6 min after 1 mg intravenous glucagon infusion, were 0.18 nmol/L and 0.77 nmol/L, respectively. Therefore, we started Glimepiride (Sanofi-Aventis) at 0.05 mg/ kg/day and gradually tapered the insulin dosage. The Glimepiride dosage reached 0.09 mg/kg/day when insulin therapy was discontinued completely and follow-up HbA1c level was 6.6% (49 mmol/mol). Since PNDM was diagnosed within the first six months of life and responsive to oral sulfonylurea, we sequenced his KCNJ11 gene. Apart from Tourette syndrome and attention deficithyperactivity disorder, he did not have other cognitive, language or motor function impairment. He had been receiving Glimepiride treatment for almost 11 years and tolerates it well.
3.
Result and discussion
The index patient had a heterozygous missense mutation at codon 167 (c499A>T) (Fig. 2A) that resulted in a substitution of isoleucine by phenylalanine. We used restriction analysis with restriction enzyme MslI to confirm the presence of mutations in the KCNJ11 gene (Fig. 2B). This is a de novo mutation since the patient’s parents do not have this mutation. It is consistent with previous report that >90% of KCNJ11 gene-related PNDM arise spontaneously [12]. The human KCNJ11 gene encodes a membrane protein Kir6.2. The ATP-sensitive potassium channel (KATP) of the pancreatic beta cell is formed by four Kir6.2 subunits and four sulfonylurea subunits in an octomeric structure [4]. The four Kir6.2 subunits form the pore of ATP-sensitive potassium channel. Residues L164 to F168 construct a hydrophobic girdle and are the narrowest part of the channel. This region is thought to be the intracellular gate and mutation of
Fig. 2 – (A) Gene sequencing figure of the patient with heterozygous c.499A>T mutation. (B) Restriction analysis of the amplification products of the KCNJ11 gene with restriction enzyme MslI at 37 8C. PCR product is 720 bps. Normal allele are 273, 315, 132 bps and mutant allele 273, 447 bps, respectively.
individual residues affects the opening frequency and duration of the channel [17]. The mutation Kir6.2-I167F we identified lies within this region. Although a functional study was not performed in Kir6.2I167F, it has been carried out in a different mutation at the same codon, the Kir6.2-I167L (c.499A>C). Shimomura et al. demonstrated that both heterozygous and homomeric mutants of I167L reduced the ATP sensitivity and increased the current of the KATP channel. This effect is caused by an increasing intrinsic open probability of the KATP channel, which prevents insulin secretion from pancreatic beta cell and results in neonatal diabetes [18]. The change of amino acid in
diabetes research and clinical practice 104 (2014) e29–e32
e31
Fig. 3 – The spectrum of mutations causing PNDM within the sequence of Kir6.2 in Han Chinese. TM1 denotes first transmembrane domain and TM2, second transmembrane domain; N,N-terminal; C,C-terminal.
I167L is between aliphatic amino acids, but the I167F we identified results in a more radical change from aliphatic to aromatic amino acid. To the best of our knowledge, four reports of KCNJ11 mutation in neonatal diabetes of Chinese have been reported in the literature (Fig. 3). These patients were treated with insulin at first and all shifted to sulfonylurea successfully. One R201C [15], one R201H [12] and two V59M [13,14] mutations were identified among them and all of these mutations had been reported previously [11]. By contrast, an 18-year-old Korean patient with an R201H mutation who did not respond to sulfonylurea treatment has been reported recently. The reason for unsuccessful switch to sulfonylurea may be the long disease process resulting in pancreatic beta-cell function failure [19]. The Kir6.2-I167F is the first novel mutation reported in ethnic Chinese. In 2012, Li et al. reviewed the clinical manifestation of 40 neonatal diabetes patients in the available Chinese literature. Among them, two patients had an intracranial hemorrhage, similar to our patient. One patient had epilepsy and 19 patients had intrauterine growth restriction. Genetic studies were carried out in three patients only [13]. Four patients received sulfonylurea and insulin (including the 3 patients who had genetic studies), 24 patients received insulin treatment only and the treatment modalities of the remaining patients were not mentioned [20]. Early genetic analysis in neonatal diabetes may change life quality dramatically. Once a mutation in the KCNJ11 or ABCC8 gene is confirmed, insulin therapy may be switched to oral sulfonylurea.
4.
Conclusion
In summary, we identified a novel Kir6.2-I167F mutation causing PNDM in a Han Chinese, which is also the first reported case of PNDM with KCNJ11 mutation in Taiwan. Successful treatment with oral sulfonylurea in our patient reemphasized the importance of early genetic analysis in neonatal diabetes.
Conflict of interest The authors declare that there are no conflicts of interest.
Acknowledgments This study was supported by grants from Medical ResearchVGH and National Science Council-NSC 96-2314-B-075-018MY3, Taiwan/ROC.
references
[1] Shield JP, Gardner RJ, Wadsworth EJ, Whiteford ML, James RS, Robinson DO, et al. Aetiopathology and genetic basis of neonatal diabetes. Arch Dis Child 1997;76:F39–42. [2] von Mu¨hlendahl KE, Herkenhoff H. Long-term course of neonatal diabetes. N Engl J Med 1995;333:704–8. [3] Slingerland AS, Shields BM, Flanagan SE, Bruining GJ, Noordam K, Gach A, et al. Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live births. Diabetologia 2009;52:1683–5. [4] Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004;350:1838–49. [5] Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, et al. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 2004;53:2713–8. [6] Njølstad PR, Søvik O, Cuesta-Mun˜oz A, Bjørkhaug L, Massa O, Barbetti F, et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 2001;344:1588–92. [7] Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997;15:106–10. [8] Babenko AP, Polak M, Cave´ H, Busiah K, Czernichow P, Scharfmann R, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006;355:456–66. [9] Vaxillaire M, Populaire C, Busiah K, Cave´ H, Gloyn AL, Hattersley AT, et al. Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes 2004;53:2719–22. [10] Massa O, Iafusco D, D‘Amato E, Gloyn AL, Hattersley AT, Pasquino B, et al. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat 2005;25:22–7. [11] Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 2005; 54:2503–13. [12] Xiao X, Wang T, Li W, Song H, Gong C, Diao C, et al. Transfer from insulin to sulfonylurea treatment in a Chinese patient with permanent neonatal diabetes mellitus due to a KCNJ11 R201H mutation. Horm Metab Res 2009;41:580–2. [13] Sang Y, Ni G, Gu Y, Liu M. KCNJ11 gene mutation in 3 cases with neonatal diabetes mellitus. Chin J Endocrinol Metab 2010;26:682–3. [14] Sang Y, Ni G, Gu Y, Liu M. AV59M KCNJ11 gene mutation leading to intermediate DEND syndrome in a Chinese child. J Pediatr Endocrinol Metab 2011;24:763–6.
e32
diabetes research and clinical practice 104 (2014) e29–e32
[15] Wang SY, Zhang LJ, He ZQ, Tian Q, Li XD. Neonatal diabetes mellitus caused by KCNJ11 mutation: a case report. CJCP 2012;14:73–5. [16] Mak CM, Lee CY, Lam CW, Siu WK, Hung VC, Chan AY. Personalized medicine switching from insulin to sulfonylurea in permanent neonatal diabetes mellitus dictated by a novel activating ABCC8 mutation. Diagn Mol Pathol 2012;21:56–9. [17] Haider S, Antcliff JF, Proks P, Sansom MS, Ashcroft FM. Focus on Kir6.2: a key component of the ATP-sensitive potassium channel. J Mol Cell Cardiol 2005;38:927–36.
[18] Shimomura K, Ho¨rster F, de Wet H, Flanagan SE, Ellard S, Hattersley AT, et al. A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain. Neurology 2007;69:1342–9. [19] Heo JW, Kim SW, Cho EH. Unsuccessful switch from insulin to sulfonylurea therapy in permanent neonatal diabetes mellitus due to an R201H mutation in the KCNJ11 gene: a case report. Diabetes Res Clin Pract 2013;100(1):e1–2. [20] Li YH, Yuan TM, Yu HM. Neonatal diabetes mellitus in China: a case report and review of the Chinese literature. Clin Pediatr (Phila) 2012;51:366–73.