ABCMdb

ABCC8 p.Cys1000*

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[hide] Mutational analysis of ABCC8, KCNJ11, GLUD1, HNF4A... Endocr J. 2014;61(9):901-10. Epub 2014 Jul 8. Sang Y, Xu Z, Liu M, Yan J, Wu Y, Zhu C, Ni G
Mutational analysis of ABCC8, KCNJ11, GLUD1, HNF4A and GCK genes in 30 Chinese patients with congenital hyperinsulinism.
Endocr J. 2014;61(9):901-10. Epub 2014 Jul 8., [PMID:25008049]

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We conducted a cohort study to elucidate the molecular spectrum of congenital hyperinsulinism (CHI) in Chinese pediatric patients. Thirty Chinese children with CHI were chosen as research subjects, 16 of whom were responsive to diazoxide and 13 of whom were not (1 patient was not given the drug for medical reasons). All exons of the adenosine triphosphate (ATP)-sensitive potassium channel (KATP channel) genes KCNJ11 and ABCC8, the hepatocyte nuclear factor 4 alpha (HNF4A) gene, and the Glucokinase (GCK) gene as well as exons 6 and 7 and 10-12 of the glutamate dehydrogenase 1 (GLUD1) gene were amplified from genomic DNA and directly sequenced. Mutations were identified in 14 of 30 patients (47%): 3 in GLUD1 (10%) and 11 in the KATP channel genes (37%). Six patients had paternally derived monoallelic KATP channel mutations predictive of the focal CHI form. We found a novel de novo ABCC8 mutation, p. C1000*, a novel paternally inherited ABCC8 mutation, D1505H, and a dominantly inherited ABCC8 mutation, R1217K. The GLUD1 activating mutation R269H was found in 2 patients: 1 de novo and the other paternally inherited. A de novo S445L mutation was found in 1 patient. No significant HNF4A or GCK mutations were found. CHI has complex genetic onset mechanisms. Paternally inherited monoallelic mutations of ABCC8 and KCNJ11 are likely the main causes of KATP-CHI in Chinese patients. Glutamate dehydrogenase-CHI is the second most common cause of CHI, while HNF4A and GCK are rare types of CHI in Chinese patients.

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63 A paternally inherited mutation, p.C1000*, was found in patient 21 (Supplementary Fig. 1D), whereas the de novo mutations D1505H, Q474R and p.R598* were found in patient 22 (Supplementary Fig. 1E), 26 (Supplementary Fig. 1F) and 30 (Supplementary Fig. 1G), respectively. Login to comment
76 Parent of origin Mutations 1* F 1 4.7 2.02 14.33 38 N N N P629PfsX17 Parental ABCC8 -C1887delc 2 M 3 3.5 1.52 17.4 128 N - - - - - 3 M 1 5.2 2.45 16.69 29 N - - - - - 4* M 1 4.4 2.54 34.96 128 N N N p.W288* Paternal ABCC8 -c.863G>A 5* F 165 4.2 1.8 9 77 N N Y A640V De Novo ABCC8 -c.1919C>T p.Q1196* Paternal ABCC8 -c.3286C>T 6* M 180 3.6 1.45 10.47 111 Y Y Y R269H De Novo GLUD1 -c.978G>A 7 M 76 4.2 1.8 43.51 95 N - - - - - 8 F 120 4.3 2.4 9.65 31 N - - - - - 9 F 2 2.3 1.6 5.34 47 N - - - - - 10 M 180 2.7 1.37 17.45 22 Y - - - - - 11 M 120 3.5 2.29 16.92 17 Y - - - - - 12* M 240 3.5 2.17 8.1 88 Y Y Y S445L De NovoGLUD1 -c.1506C>T 13* M 150 3.2 1.9 8.7 175 Y Y Y R269H Paternal GLUD1 -c.978G>A 14* F 1 4.2 2.01 9.18 44 Y N Y R1217K MaternalABCC8 -c.3650G>A 15* F 120 3.6 1.82 0.87 31 Y Y N R1493Q Paternal ABCC8 -C4487G>A 16* M 45 4.2 1.7 17.4 44 N Y N Q235E Paternal KCNJ11 -C703C>G 17 F 1 4.9 3.43 10.9 35 Y - - - - - 18 M 120 2.8 0.79 16.54 41 Y - - - - - 19 M 90 2.9 2.42 8.3 58 Y - - - - - 20* M 330 3.2 2.5 12.8 175 Not Used N Not Used R495Q Paternal ABCC8 -c.1484G>A 21* M 80 3.4 0.67 3.1 36 N Y N p.C1000* Paternal ABCC8 -c.3000C>A 22* F 1 5.28 1.04 22.94 46 N Y N D1505H De NovoABCC8 -c.4513G>C 23 F 240 3.25 2.24 4.69 26 Y - - - - - 24 M 240 3.5 1.9 12.96 31 Y - - - - - 25 F 1 3.6 1.06 30.8 54 Y - - - - - 26* F 2 4.5 1.5 8.8 38 N Y N Q474R De NovoABCC8 -c.1421A>G 27 F 30 3.5 1.03 10.37 27 Y - - - - - 28 M 120 5.45 1.36 11.48 48 N - - - - - 29 M 720 4.3 2.2 8.3 21 Y - - - - - 30* F 1 4.05 1.96 1.41 62 N Y N p.R598* De Novo ABCC8 -c.1792C>T * Patients with mutation results mutation in KCNJ11. Login to comment
77 The p.C1000*, D1505H, and Q235E mutations have never been described before. Login to comment
107 Five patients carried paternally inherited ABCC8 mutations including P629PfsX17, p.W288*, R495Q, R1493Q and p.C1000*. Login to comment
145 A) Patient 5 showed a c.4487 G>A mutation (R1493Q); B) patient 20 showed a c.1484 G>A mutation (R495Q); C) patient 14 showed a c.3650G>A mutation (R1217K); D) patient 21 showed a c.3000C>A mutation (p.C1000*); E) patient 22 showed a c.4513G>C mutation (D1505H); F) patient 26 showed a c.1421A>G mutation (Q474R); G) patient 30 showed a c.1792C>T mutation (p.R598*). Login to comment