ABCMdb

PMID: 9618169

Nestorowicz A, Glaser B, Wilson BA, Shyng SL, Nichols CG, Stanley CA, Thornton PS, Permutt MA
Genetic heterogeneity in familial hyperinsulinism.
Hum Mol Genet. 1998 Jul;7(7):1119-28., [PubMed]

Sentences

No. Mutations Sentence Comment

63 ABCC8 p.Asn188Ser ABCC8 p.Phe591Leu ABCC8 p.His125Gln ABCC8 p.Arg74Gln ABCC8 p.Asn406Asp Mutations within the SUR1 gene Patient Exon or intron Nucleotide changea Codona predicted effect Domainb Restriction site change Frequency (%) HI chromosomes (n = 88) Segregation demonstrated Frequency 200 normal chromosomes A1 exon 2 221G→A R74Q Tm PstI 1 (1.1%) NA 0 B2d exon3 375C→G H125Q Tm DdeIc 1 (1.1%) NA 0 C3e exon 4 563A→G N188S Tm TspRI 1 (1.1%) yes 0 D4 exon 6 949delC 317fs/ter Tm Bsp1286I 1 (1.1%) yes 0 E5 exon 8 1216A→G N406D Tm XcmI 1 (1.1%) NA 0 F6f intron 10 1630+1G→T aberrant splicing Tm BsrI 2 (2.3%) yes 0 G7 exon 12 1773C→G F591L Tm BsoF1 1 (1.1%) no 0 H8 exon 13 1893delT 631fs/ter Tm BstNI 1 (1.1%) yes 0 F6f intron 15 2117-1G→A aberrant splicing NBF-1 PstI 1 (1.1%) yes 0 I9 exon 24 2860C→T Q954X - BstNI 1 (1.1%) yes 0 J10g exon 28 3416C→Th T1139M Tm NlaIII 1 (1.1%) yes 0 K11 exon 29 3644G→A R1215Q Tm NciI 1 (1.1%) yes 0 J10g intron 32 3992-9G→Ai aberrant splicing NBF-2 NciI 4 (4.5%) yes 0 C3e intron 32 3992-3C→G aberrant splicing NBF-2 AvaI 1 (1.1%) yes 0 L12 exon 34 4135G→C G1379R NBF-2 EagI 1 (1.1%) yes 0 M13 exon 34 4144G→A G1382S NBF-2 BglI 1 (1.1%) yes 0 B2d exon 34 4162delTTCi,j delF 1388 NBF-2 BseRI 1 (1.1%) yes 0 J10g exon 34 4181G→Ah R1394H NBF-2 DraIII 1 (1.1%) yes 0 N14 exon 35 4310G→Ai aberrant splicing NBF-2 MspI 1 (1.1%) yes 0 O15 exon 37 4525insCGGCTT insertion of AlaSer ft d 1508 NBF-2 PvuIIk 1 (1.1%) yes 0 after codon 1508 aNucleotide and codon positions are according to the full-length human SUR1 cDNA sequence incorporating the alternative splicedform of exon 17 (GenBank accession nos L78208 and L78216). Login to comment 141 ABCC8 p.Phe591Leu For proband G7, BsoF1 restriction enzyme analysis indicated that although the proband possessed a Phe591Leu mutation in the heterozygous state, this mutation was neither present in the proband`sparentsnorintwounaffectedsiblings(datanotshown). Login to comment 142 ABCC8 p.Phe591Leu Nucleotide sequence analyses confirmed the absence of the Phe591Leu mutation in all first-degree relatives of proband G7. Login to comment 143 ABCC8 p.Phe591Leu Since the results of extended haplotype analyses for kindred G were consistent with Mendelian inheritance for all offspring (data not shown), these data suggest that the Phe591Leu substitution occurred de novo in proband G7. Login to comment 144 ABCC8 p.Phe591Leu With the exception of the Phe591Leu mutation, all other missense mutations examined co-segregated with the HI phenotype and displayed Mendelian inheritance (Fig. 4b and data not shown). Login to comment 192 ABCC8 p.Gly716Val Furthermore, an analogous mutation (G716V) at Gly2 in the Walker A sequence motif in NBF-1 of the SUR1 protein has also been described in a HI patient (14). Login to comment 200 ABCC8 p.Asn188Ser ABCC8 p.Phe591Leu ABCC8 p.His125Gln ABCC8 p.Arg74Gln ABCC8 p.Asn406Asp A model for SUR1 (29) predicts that the remaining seven missense mutations (Arg74Gln, His125Gln, Asn188Ser, Asn406Asp, Phe591Leu, Thr1139Met, Arg1215Gln) are located either within transmembrane segments or are present on the extracellular or cytoplasmic loops connecting adjacent trans- membranehelices.Theidentificationofthesemissensemutations in HI patients provides a basis for further studies to elucidate the functions of these transmembrane domains in SUR1 and KATP channel activity. Login to comment 201 ABCC8 p.Phe591Leu ABCC8 p.His125Gln We have found that the His125Gln, Phe591Leu, Thr1139Met and Arg1215Gln mutations result in various reductions in the sensitivity of KATP channels to stimulation by MgADP in vitro (S.-L.Shyng et al., unpublished data). Login to comment 202 ABCC8 p.Phe591Leu Furthermore, increased sensitivity of KATP channel activity to inhibition by ATP was observed in channels containing the Phe591Leu mutation. Login to comment 203 ABCC8 p.Arg74Gln ABCC8 p.Asn406Asp The functional significance of the Arg74Gln and Asn406Asp mutations upon SUR1 regulation of KATP channel activity are currently unknown. Login to comment 233 ABCC8 p.His125Gln To detect the His125Gln mutation, which did not alter a restriction enzyme site, PCR-directed site-specific mutagenesis was used to incorporate a DdeI restriction site into products derived from wild-type alleles. Login to comment 242 ABCC8 p.Gly716Val Genomic DNA samples were also analyzed for the presence of six previously described mutations (1671-20A→G, G716V, 2291-1G→A, 3993-9G→A, ∆F1388 and G1479R) by PCR amplification of relevant exons and flanking intron-exon boundaries, followed by restriction enzyme digestion as described in detail elsewhere (12-15). Login to comment