ABCMdb

PMID: 19475716

Sandal T, Laborie LB, Brusgaard K, Eide SA, Christesen HB, Sovik O, Njolstad PR, Molven A
The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy.
Clin Genet. 2009 May;75(5):440-8., [PubMed]

Sentences

No. Mutations Sentence Comment

11 ABCC8 p.Thr1531Ala ABCC8 p.Cys267* ABCC8 p.Ile462Val ABCC8 p.Trp231Arg ABCC8 p.Gln917* Altogether, 16 different ABCC8 mutations (including the novel alterations W231R, C267X, IVS6-3C.G, I462V, Q917X and T1531A) were identified. Login to comment 12 ABCC8 p.Val21Asp ABCC8 p.Arg1493Trp The mutations IVS1011G.T, R1493W and V21D occurred in five, three and two families, respectively. Login to comment 106 ABCC8 p.Thr1531Ala ABCC8 p.Cys267* ABCC8 p.Ile462Val ABCC8 p.Trp231Arg ABCC8 p.Gln917* Six of the ABCC8 mutations (W231R, C267X, IVS6-3C.G, I462V, Q917X, and T1531A) were novel, whereas the remaining have been previously reported and in several cases functionally characterized (Table 2). Login to comment 107 ABCC8 p.Val21Asp ABCC8 p.Arg1493Trp The mutations IVS1011G.T, R1493W and V21D were recurrent mutations as they were observed in five, three and two independently recruited families, respectively. Login to comment 109 ABCC8 p.Val187Asp ABCC8 p.Leu503Pro ABCC8 p.Val21Asp ABCC8 p.Val21Asp ABCC8 p.Arg248* ABCC8 p.Cys267* ABCC8 p.Ile462Val ABCC8 p.Trp231Arg ABCC8 p.Gln917* ABCC8 p.Arg1493Trp ABCC8 p.Arg1493Trp ABCC8 p.Arg1493Trp ABCC8 p.Arg1493Trp ABCC8 p.Gly1400Arg Clinical characteristics of Norwegian CHI patients carrying mutations in ABCC8 Proband Sex Birth weight (g)/gestation length (weeks)a Treatment Mutationsd Medicalb Surgeryc Maternal chromosome Paternal chromosome Hypo-N3 F 6190/38 Deceased Yes (S) R1493W R1493W Hypo-N6 M 5340/38 Somatostatin, diet (FM, PEG) No V21D V21D Hypo-N8 F 5740/37 Insulin Yes (S) G1400R R1493W Hypo-N9 F 5130/40 Diet (FM) Yes (S) - IVS1011G.T Hypo-N11 M 4000/38 None No - G1478Re Hypo-N14 M 5000/40 Somatostatin, diet (FM, PEG) No - IVS1011G.T Hypo-N16 F 3780/38 Diet (FM) No - C267X Hypo-N19 F 5240/40 Somatostatin, diet (FM, PEG) No IVS1011G.T T1531Af Hypo-N22 M 4500/39 Diazoxide Yes (S) IVS6-3C.G, I462V Q917X Hypo-N23 F 4860/38 Insulin Yes (S) P1413Lg IVS1011G.Tg Hypo-N25 M 3910/34 Insulin Yes (S) V21Dg E490Xg Hypo-N26 M 3790/35 Diet (FM, PEG) Yes (H) V187D R248X Hypo-N29 F 3350/37 None Yes (P) - IVS1011G.T Hypo-N30 F 3800/37 Diazoxide No W231R L503P Hypo-N31 M 4340/40 None Yes (P) - R1493W a All cases had birth weights 12 standard deviation scores except for Hypo-N29 whose score was 11. b Current therapy is given. Login to comment 122 ABCC8 p.Val187Asp ABCC8 p.Leu503Pro ABCC8 p.Val21Asp ABCC8 p.Val21Asp ABCC8 p.Pro1413Leu ABCC8 p.Thr1531Ala ABCC8 p.Cys267* ABCC8 p.Ile462Val ABCC8 p.Trp231Arg ABCC8 p.Gln917* ABCC8 p.Arg1493Trp ABCC8 p.Arg1493Trp ABCC8 p.Arg1493Trp ABCC8 p.Gly1400Arg ABCC8 p.Gly1478Arg ABCC8 p.Glu490* We classified the mutations as either MnMn Hypo-N3 R1493W MMMM Mn Mn Hypo-N6 V21D MM MnMn Hypo-N8 G1400R / R1493W MM nnMn Hypo-N9 IVS10 Mn Hypo-N11 G1478R Mn nnMn Hypo-N16 C267X Mn Mn Hypo-N19 IVS10 / T1531A MM Mn nn Hypo-N29 IVS10 Mn Mn Hypo-N30 W231R / L503P MM MM x Hypo-N23 IVS10 / P1413L MM x Hypo-N14 IVS10 Mn Hypo-N22 IVS6 (I462V) / Q917X MM Hypo-N25 V21D / E490X MM xx Hypo-N26 V187D / R248 X MM x Hypo-N31 R1493W nnMnMnMn nnnnMn MnMn MM MnMn Mn nnnn Fig. 1. Login to comment 131 ABCC8 p.Thr1531Ala ABCC8 p.Gly1478Arg In families Hypo-N11 and Hypo-N19, the mutations G1478R and T1531A occurred de novo as they were not seen in blood samples from the parents. Login to comment 133 ABCC8 p.Val187Asp ABCC8 p.Leu503Pro ABCC8 p.Val21Asp ABCC8 p.Pro1413Leu ABCC8 p.Arg248* ABCC8 p.Thr1531Ala ABCC8 p.Cys267* ABCC8 p.Trp231Arg ABCC8 p.Gln917* ABCC8 p.Arg1493Trp ABCC8 p.Gly1400Arg ABCC8 p.Gly1478Arg ABCC8 p.Glu490* ABCC8 mutations found in Norwegian CHI patientsa Nucleotide change Location Amino acid change Mutation type PSIC score PD Number of families Reference c.62 T.A Exon 1 V21D Mis 1.96 PoD 2 (24) c.560 T.A Exon 4 V187D Mis 2.01 PrD 1 (2) c.691 T.C Exon 5 W231R Mis 4.03 PrD 1 NR c.742 C.T Exon 5 R248X Non - - 1 (34, 42) c.801 C.A Exon 5 C267X Non - - 1 NR IVS6-3C.G Intron 6 - AS - - 1 NR c.1384 A.G Exon 9 I462V Mis 0.62 PrB 1 NR c.1468 G.T Exon 10 E490X Non - - 1 (43) c.1508 T.C Exon 10 L503P Mis 2.36 PrD 1 (24) IVS1011G.T Intron 10 - AS - - 5 (44) c.2749 C.T Exon 23 Q917X Non - - 1 NR c.4198 G.A Exon 35 G1400R Mis 2.37 PrD 1 (42) c.4238 C.T Exon 35 P1413L Mis 2.76 PrD 1 (25) c.4432 G.A Exon 37 G1478R Mis 2.37 PrD 1 (14, 31) c.4477 C.T Exon 37 R1493W Mis 2.79 PrD 3 (26) c.4591 A.G Exon 38 T1531A Mis 1.93 PoD 1 NR AS, aberrant splicing; Mis, missense; NR, not previously reported; Non, nonsense; PD, pathogenic description; PoD, possibly damaging; PrB, predicted to be benign; PrD, probably damaging; PSIC, position-specific independent counts. Login to comment 139 ABCC8 p.Gly1478Arg The sixth heterozygous subject (Hypo-N11) carried the G1478R mutation and had a mild phenotype. Login to comment 140 ABCC8 p.Gly1478Arg DNA from his healthy parents did not contain G1478R, suggesting dominant CHI caused by a de novo mutation (31). Login to comment 142 ABCC8 p.Thr1531Ala This proband had an IVS1011G.T mutation inherited from the mother and a de novo T1531A mutation likely to have arisen on the paternal allele. Login to comment 156 ABCC8 p.Gly1478Arg One proband had a heterozygous de novo G1478R mutation, which recently has been reported to cause a milder, dominantly acting form of the disease (31). Login to comment 168 ABCC8 p.Val187Asp ABCC8 p.Leu503Pro ABCC8 p.Val21Asp ABCC8 p.Pro1413Leu ABCC8 p.Arg248* ABCC8 p.Arg1493Trp ABCC8 p.Gly1400Arg ABCC8 p.Gly1478Arg ABCC8 p.Glu490* A largenumber (.150)ofABCC8 alterations have been reported to cause CHI (19) including 10 of the mutations observed in this study (V21D, V187D, R248X, E490X, L503P, IVS1011G.T, G1400R, P1413L, G1478R, and R1493W). Login to comment 172 ABCC8 p.Cys267* ABCC8 p.Gln917* Two of these (C267X and Q917X) are nonsense mutations, which have a very strong pathogenic potential because they induce premature termination of the SUR1 protein. Login to comment 173 ABCC8 p.Thr1531Ala ABCC8 p.Ile462Val ABCC8 p.Trp231Arg Three novel variants (W231R, I462V, and T1531A) are missense mutations. Login to comment 174 ABCC8 p.Trp231Arg W231R is predicted to be probably damaging by the PSCI score (Table 2). Login to comment 176 ABCC8 p.Trp231Arg We therefore conclude that a pathogenic effect of W231R is very likely. Login to comment 177 ABCC8 p.Thr1531Ala ABCC8 p.Ile462Val The mutations I462V and T1531A, however, are positioned outside the TMD and NBD of SUR1 and have lower PSIC scores. Login to comment 178 ABCC8 p.Ile462Val I462V was identified on the maternal allele in both affected brothers of the Hypo-N22 family. Login to comment 180 ABCC8 p.Ile462Val Because IVS6-3C.G is located in the splice acceptor recognition signal, we predict that it will cause aberrant splicing of exon 6 and that I462V therefore may affect the function of the SUR1 protein to a lesser degree. Login to comment 181 ABCC8 p.Thr1531Ala Concerning T1531A, it must have occurred de novo on the paternal chromosome of the affected child, assuming that the disease in family Hypo-N19 was inherited recessively. Login to comment 182 ABCC8 p.Thr1531Ala This would predict T1531A to be pathogenic. Login to comment 183 ABCC8 p.Val21Asp Moreover, its PSIC score is similar to that of the disease-causing V21D mutation (Table 2). Login to comment 187 ABCC8 p.Val187Asp One example is V187D that is located in TMD0 and was found in family Hypo-N26. Login to comment 189 ABCC8 p.Val187Asp V187D is a founder mutation in Finland (2), and further investigation revealed that the mother of the proband was of Finnish ancestry. Login to comment