| Full gene name: | ATP-binding cassette, sub-family C (CFTR/MRP), member 8 |
|---|---|
| Entrez Gene ID: | 6833 |
| Location: | 11p15.1 |
| Synonyms: | TNDM2, ABC36, HHF1, PHHI, MRP8, HI, SUR, SUR1, HRINS, SUR1delta2 |
| Type: | protein-coding |
SNPs given by the user that are near or inside this gene:
| SNP | Distance (bp) | Direction |
|---|---|---|
| rs5215 | 5802 | downstream |
The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a modulator of ATP-sensitive potassium channels and insulin release. Mutations and deficiencies in this protein have been observed in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent diabetes mellitus type II, an autosomal dominant disease of defective insulin secretion. Alternative splicing of this gene has been observed; however, the transcript variants have not been fully described. [provided by RefSeq, Jul 2008]
| OMIM ID: | `OMIM ID 600509 `_ |
|---|
Allelic Variants (Selected Examples)
.0001 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In a child with hyperINSULINemic hypoglycemia (256450), born of consanguineous parents, Thomas et al. (1995) showed that a cloned pancreatic cDNA product had a 109-bp deletion within the NBF2 region of SUR, which corresponded to skipping of exon chi. The deletion caused disruption of the NBF2 consensus sequence by generating a frameshift and ultimately a premature stop signal 24 codons past the deletion. In genomic DNA, a homozygous G-to-A point mutation was found in the 3-prime end of the skipped exon. The recognition site for the restriction endonuclease MspI was destroyed by this base change. Both affected children in the family were homozygous, whereas the parents and 2 unaffected sibs were heterozygous. Twelve other affected children from 6 families of Saudi Arabian origin and 1 family of German origin were homozygous for the G-to-A point mutation, as demonstrated by loss of the MspI recognition site. The G-to-A mutation involved the last nucleotide of the skipped exon. Thomas et al. (1995) cited other instances in which G-to-A point mutations at this position had been observed to result in skipping of the exon containing the mutation.
.0002 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In 2 sibs with hyperINSULINemic hypoglycemia (256450), born of consanguineous parents, Thomas et al. (1995) found a mutation in the 3-prime splice site sequence preceding the NBF2 region. The G-to-A mutation destroyed an NciI restriction endonuclease recognition site, and homozygous loss of this site cosegregated with disease phenotype within the family. The G-to-A transition occurred at the ninth nucleotide from the 3-prime end of the intron preceding exon alpha, the first NBF2 exon. In a construct containing the mutation, 3 cryptic 3-prime splice sites within exon alpha were used in place of the wildtype splicing site.
Nestorowicz et al. (1996) demonstrated that this mutation in the SUR1 gene and the F1388del mutation (600509.0006) account for approximately 88% of hyperINSULINism-associated chromosomes in Ashkenazi Jewish patients. Haplotype analysis with microsatellite markers flanking the gene revealed that the delF1388 mutation, reported only in Ashkenazi probands, occurred on 2 related extended haplotypes. By contrast, the second, more common mutation (3992-9G-A) was associated with 9 different intergenic haplotypes and was reported in non-Jewish hyperINSULINism patients as well. Glaser et al. (1999) evaluated disease-associated chromosomes from 41 Ashkenazi Jewish and 2 non-Jewish hyperINSULINism patients carrying the 3992-9G-A mutation by assessing haplotypes defined by 9 common single-nucleotide polymorphisms (SNPs), 6 in the SUR1 gene and 3 in the closely linked KIR6.2 gene. They found that all 54 chromosomes carrying this particular mutation in the Jewish patients appeared to have originated from 1 founder mutation, whereas the same mutation in chromosomes from non-Jewish patients originated independently.
.0003 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In a boy with hyperINSULINemic hypoglycemia (256450), born of consanguineous Malaysian parents, Thomas et al. (1996) found that the 6 exons that compose the NBF2 region of SUR had wildtype sequence. The NBF1 region, which is encoded by 8 exons that span approximately 8.2 kb of genomic sequence, shows strong homology with the NBF2 region and the NBF regions of other superfamily members. In of the proband of this family, a homozygous G-to-T transversion was found in the second exon (106-bp exon) of the NBF1 region. The point mutation was predicted to substitute a valine for the second glycine residue, G716V, of the Walker A motif of the NBF1 region, thereby altering a site that is conserved among all members of the ATP-binding-cassette superfamily. The mutation resulted in the loss of a BbvI restriction site allowing demonstration that the affected child was homozygous for the mutation, the parents heterozygous, and an unaffected sib homozygous for the wildtype allele.
.0004 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In 2 brothers with hyperINSULINemic hypoglycemia (256450), born of nonconsanguineous German parents, Thomas et al. (1996) identified compound heterozygosity for 2 mutations located in sequences predicted to affect RNA processing of the SUR transcript. The first mutation was a G-to-A transition located at the -1 residue, within the 3-prime splice site of the fifth exon (99-bp exon) of the NBF1 region. The transition destroyed a BstNI restriction site. A G-to-A mutation in the -1 invariant residue in the 3-prime splice site in other genes has been found to result in 100% skipping of the involved exon or in both exon skipping and cryptic 3-prime splice site activation. The second mutation was a branch point mutation (600509.0005) at nucleotide -20 of the 146-bp exon preceding the NBF1 encoding region. The presence of this point mutation disrupted an invariant A residue of the branch-point consensus. This A-to-G change resulted in the destruction of an engineered SpeI restriction endonuclease site. Restriction analysis demonstrated that the first mutant allele was of maternal origin and the second of paternal origin. An unaffected brother was homozygous for the wildtype alleles.
.0005 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
See 600509.0004 and Thomas et al. (1996).
.0006 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In Ashkenazi Jewish families with hyperINSULINemic hypoglycemia (256450), Nestorowicz et al. (1996) identified a 3-bp deletion in exon 34 of the SUR gene, resulting in deletion of phenylalanine-1388. The deletion was associated with a specific haplotype (H1) in the D11S1901-D11S1310 region. The mutation led to the generation of a novel BseR1 restriction site.
.0007 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
Dunne et al. (1997) identified a G-to-A transition in the terminal nucleotide of exon 35 of the SUR gene in homozygous state in a child from consanguineous Saudi Arabian parents. The child and 2 sibs had persistent hyperINSULINemic hypoglycemia of infancy (256450). The 2 affected sibs had undergone partial pancreatectomy for the disorder. The proband was born at term after a normal gestation, weighed 4.25 kg, and had macrosomia and plethora, features of in utero hyperINSULINism. Two partial pancreatectomies were required for control of hypoglycemia. Histologic examination of the pancreas revealed diffuse nesidioblastosis. The parents were heterozygous for the G-A mutation. (The mutations previously discovered by Thomas et al. (1995), (1996) and by Nestorowicz et al. (1996) were not mentioned by Dunne et al. (1997).)
.0008 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In a sporadic case of persistent hyperINSULINemic hypoglycemia of infancy (256450) due to focal adenomatous hyperplasia, Verkarre et al. (1998) found a 4058G-C transversion in exon 33 of the paternally derived SUR gene, leading to an arg1353-to-pro (R1353P) amino acid substitution. The father was constitutionally heterozygous for the same mutation. This was 1 of 12 cases in which loss of maternal alleles of the 11p15 chromosomal region had been found, limited to the hyperplastic lesions of focal adenomatous hyperplasia.
.0009 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In a sporadic case of persistent hyperINSULINemic hypoglycemia of infancy (256450) due to focal adenomatous hyperplasia, Verkarre et al. (1998) found a 4261C-T transversion in exon 33 of the paternally derived SUR gene, leading to an arg1421-to-cys (R1421C) amino acid substitution. The father was constitutionally heterozygous for the same mutation. This was 1 of 12 cases in which loss of maternal alleles of the 11p15 chromosomal region had been found, limited to the hyperplastic lesions of focal adenomatous hyperplasia.
Matsuo et al. (2000) analyzed the functional consequences of the R1421C mutation, which they referred to as R1420C. They showed that the mutation lowers the affinity of the nucleotide-binding fold 2 (NBF2) for ATP and ADP and abolishes the ability of nucleotide binding at NBF2 to stabilize 8-azido-ATP binding at NBF1. In addition, the mutation decreases the expression of potassium-ATP channels, and a smaller current in R1420C-PHHI beta cells leads to enhanced INSULIN secretion.
.0010 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In 2 unrelated sporadic cases of persistent hyperINSULINemic hypoglycemia of infancy (256450) due to focal adenomatous hyperplasia, Verkarre et al. (1998) demonstrated loss of heterozygosity of the 11p15 region in the maternal allele and a point mutation in the paternally derived SUR allele: a 4480C-T transition in exon 37 leading to an arg1494-to-trp (R1494W) substitution. The father in each case was heterozygous for the R1494W mutation.
.0011 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In affected members of a Finnish family with hyperINSULINemic hypoglycemia (256450), Huopio et al. (2000) identified a heterozygous glu1506-to-lys (E1506K) mutation in the ABCC8 gene. This mutation led to a reduction, but not a complete loss, of K(ATP) channel activity. Huopio et al. (2003) characterized glucose metabolism in adults heterozygous for this mutation. They found that the mutation results in congenital hyperINSULINism in infancy, loss of INSULIN secretory capacity in early adulthood, and diabetes in middle age. Huopio et al. (2003) suggested that the disorder represents a new subtype of autosomal dominant diabetes. They noted that, except for age at presentation, the E1506K mutation causes a disorder that fulfills the criteria for a form of MODY (see 606391).
In a 6-year-old girl who was macrosomic at birth and had hyperINSULINemic hypoglycemia, Pinney et al. (2008) identified heterozygosity for what they designated the E1507K mutation in the ABCC8 gene. (Pinney et al., 2008 stated that they used numbering that included the alternatively spliced exon 17 sequence, and therefore the E1506K mutation reported by Huopio et al., 2000 is the same amino acid change as the E1507K mutation reported here.) Pinney et al. (2008) identified the E1507K in 8 other members of the family, none of whom had been suspected of having hypoglycemia, although 3 had severe symptoms, and 3 had mild symptoms consistent with hypoglycemia. The proband’s mother and younger brother were the only mutation carriers who denied ever having symptoms of hypoglycemia.
.0012 LEUCINE-SENSITIVE HYPOGLYCEMIA OF INFANCY
In a 4-year-old boy with leucine-sensitive hypoglycemia (240800), Magge et al. (2004) identified a 4058G-A transition in exon 33 of the SUR1 gene that resulted in an arg1353-to-his (R1353H) substitution. Arg1353 of SUR1 is conserved across golden hamster, European hamster, rat, mouse, fruit fly, and cricket and is also conserved between human SUR1 and isoforms of SUR2 (601439). Rubidium ion efflux assay and electrophysiologic studies of R1353H SUR1 coexpressed with wildtype Kir6.2 (600937) in simian kidney fibroblasts demonstrated partially impaired ATP-dependent potassium channel function.
.0013 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In 15 of 24 Finnish patients with hyperINSULINemic hypoglycemia (256450), Otonkoski et al. (1999) identified homozygosity or heterozygosity for a 560T-A transversion in exon 4 of the ABCC8 gene, resulting in a val187-to-asp (V187D) substitution located toward the cytosolic end of the putative fourth or fifth transmembrane domain. In vitro studies demonstrated that the presence of the V187D mutation renders the potassium channel completely nonfunctional. Parents and sibs who were carriers of the mutation were apparently asymptomatic; Otonkoski et al. (1999) postulated the presence of another mutation in heterozygous affected individuals.
.0014 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In 5 affected members of the 3-generation family (‘family 1’) with hyperINSULINemic hypoglycemia (256450) originally reported by Thornton et al. (1998), Thornton et al. (2003) identified heterozygosity for a 3-bp deletion (4159-4161) in exon 34 of the ABCC8 gene, resulting in an in-frame deletion of a serine at codon 1387 (ser1387del). The mutation was not found in 4 unaffected family members. Studies in COSm6 cells revealed that potassium channels containing the mutation were not functional. Thornton et al. (2003) noted that this mutation is immediately adjacent to the F1388del ({60509.0006}) mutation that causes recessive hyperINSULINism in Ashkenazi Jews.
.0015 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1
In an infant of Spanish descent diagnosed 3 days postnatally with hyperINSULINemic hypoglycemia (256450), Tornovsky et al. (2004) identified heterozygosity for a -64C-G transversion in the promoter of the ABCC8 gene on the paternal allele. Functional studies using a luciferase reporter vector revealed a 40% decrease in reporter gene expression for the mutant variant compared to wildtype, and the variant was not found in 100 control chromosomes tested. No mutation was found on the maternal allele. No focal lesion had been identified after near-total pancreatectomy, but the specimen was not available for reevaluation.
.0016 diabetes MELLITUS, PERMANENT NEONATAL, WITH NEUROLOGIC FEATURES
In a 27-year-old man who had permanent neonatal diabetes with severe developmental delay and generalized epileptiform activity on EEG (see 606176), Proks et al. (2006) identified heterozygosity for a de novo 394T-C transition in exon 3 of the ABCC8 gene, resulting in a phe132-to-leu (F132L) substitution. The mutation was not found in his unaffected parents or in 150 normal chromosomes.
.0017 diabetes MELLITUS, PERMANENT NEONATAL
In a 5-year-old boy with permanent neonatal diabetes mellitus (606176), Babenko et al. (2006) identified heterozygosity for a de novo leu213-to-arg (L213R) substitution.
.0018 diabetes MELLITUS, PERMANENT NEONATAL
In a 17-year-old male with permanent neonatal diabetes mellitus (606176), Babenko et al. (2006) identified heterozygosity for a de novo ile1424-to-val (I1424V) substitution.
.0019 diabetes MELLITUS, TRANSIENT NEONATAL, 2
In a 16-year-old French girl with transient neonatal diabetes mellitus (610374) who had a recurrence of diabetes at age 11 and in affected members of an unrelated 5-generation French family with transient neonatal diabetes and adult-onset type II diabetes mellitus (125853), Babenko et al. (2006) identified heterozygosity for an arg1379-to-cys (R1379C) substitution. The mutation arose de novo in the first patient. The 5-year-old female proband of the family had transient neonatal diabetes. Her father developed diabetes at age 32 that was treated with sulfonylureas, and her paternal grandmother was diagnosed with gestational diabetes and treated with diet, and a paternal great-aunt was diagnosed at age 44 with diabetes that was also treated with sulfonylureas. Babenko et al. (2006) proposed that mutations of the ABCC8 gene might give rise to a monogenic form of type II diabetes with variable expression and age at onset.
De Wet et al. (2007) performed functional studies of this mutation, which they designated R1380C, and demonstrated enhanced MgATP hydrolysis by purified isolated fusion proteins of maltose-binding protein and the second nucleotide-binding domain of ABCC8, in which the mutation is located. This increase in ATPase activity reduced the sensitivity of the channel to inhibition by MgATP and increased the whole-cell K(ATP) current. The authors noted that in pancreatic beta cells, such an increase in K(ATP) current would be expected to impair INSULIN secretion and thereby cause diabetes.
.0020 diabetes MELLITUS, TRANSIENT NEONATAL, 2
In a 2-year-old French boy with transient neonatal diabetes mellitus (610374) and in affected members of an unrelated 3-generation French family with transient neonatal diabetes and adult-onset type II diabetes mellitus (125853), Babenko et al. (2006) identified heterozygosity for a leu583-to-val (L582V) substitution. The mutation arose de novo in the first patient. In the affected family, the 5-year-old male proband and his female cousin had transient neonatal diabetes, whereas their mutation-positive fathers both developed after age 30 adult-onset type II diabetes that was treated with diet alone; and their paternal grandfather also had type II diabetes occurring later in life. Babenko et al. (2006) proposed that mutations of the ABCC8 gene might give rise to a monogenic form of type II diabetes with variable expression and age at onset.
.0021 diabetes MELLITUS, PERMANENT NEONATAL
In a patient from a cohort of 59 patients with permanent diabetes (606176) who received a diagnosis before 6 months of age and who did not have a KCNJ11 mutation, Ellard et al. (2007) identified an 215A-G transition in the ABCC8 gene, resulting in an asn72-to-ser (N72S) substitution, in combination with mosaic segmental paternal isodisomy for 11pter to 11p14. This region includes the ABCC8 gene, and thus uniparental disomy had unmasked a recessively acting mutation. The father was heterozygous for the mutation but did not have diabetes.
.0022 diabetes MELLITUS, PERMANENT NEONATAL
In a patient with permanent neonatal diabetes mellitus (606176), diagnosed before the age of 6 months, Ellard et al. (2007) identified a homozygous 1144G-A transition in the ABCC8 gene that resulted in a glu382-to-lys (E382K) substitution. The heterozygous, first-cousin parents were not diabetic.
.0023 diabetes MELLITUS, PERMANENT NEONATAL
In a patient with permanent neonatal diabetes mellitus (606176), diagnosed before the age of 6 months, the offspring of first cousins, Ellard et al. (2007) identified a homozygous mutation in the ABCC8 gene: a 3554C-A transversion resulting in an ala1185-to-glu substitution (A1185E). Neither parent was diabetic.
.0024 diabetes MELLITUS, PERMANENT NEONATAL
In a patient with permanent neonatal diabetes mellitus (606176), Ellard et al. (2007) observed compound heterozygosity for mutations in the ABCC8 gene. One allele carried a 134C-T transition resulting in a pro45-to-leu substitution (P45L); the other carried a 4201G-A transition resulting in a gly1401-to-arg substitution (G1401R; 600509.0025).
.0025 diabetes MELLITUS, PERMANENT NEONATAL
See Ellard et al. (2007) and 600509.0024.
.0026 diabetes MELLITUS, PERMANENT NEONATAL
In an infant with permanent neonatal diabetes mellitus (606176) diagnosed at the age of 5 months, Ellard et al. (2007) found heterozygosity for a mutation in the ABCC8 gene: a 257T-G transversion resulting in a val86-to-gly substitution (V86G). This was one of 8 patients with this disorder associated with a heterozygous de novo mutation in ABCC8.
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