Alternative titles; symbols
HGNC Approved Gene Symbol: ABCC8
SNOMEDCT: 44054006, 609580007, 62151007; ICD10CM: E11;
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38): 11:17,392,498-17,476,845 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.1 | Diabetes mellitus, noninsulin-dependent | 125853 | Autosomal dominant | 3 |
| Diabetes mellitus, permanent neonatal 3, with or without neurologic features | 618857 | Autosomal dominant; Autosomal recessive | 3 | |
| Diabetes mellitus, transient neonatal 2 | 610374 | 3 | ||
| Hyperinsulinemic hypoglycemia, familial, 1 | 256450 | Autosomal dominant; Autosomal recessive | 3 | |
| Hypoglycemia of infancy, leucine-sensitive | 240800 | Autosomal dominant | 3 |
Sulfonylureas are a class of drugs widely used as oral hypoglycemics to promote insulin secretion in the treatment of noninsulin-dependent diabetes mellitus (NIDDM; see 125853). These drugs interact with the sulfonylurea receptor of pancreatic beta cells and inhibit the conductance of adenosine triphosphate (ATP)-dependent potassium channels. Aguilar-Bryan et al. (1995) cloned the cDNA for the high-affinity sulfonylurea receptor. Analysis of the predicted amino acid sequence indicated that the gene is a member of the ATP-binding cassette or traffic ATPase superfamily with multiple membrane-spanning domains and 2 nucleotide-binding folds. The results suggested that the sulfonylurea receptor may sense changes in ATP and ADP concentration, affect K(ATP) channel activity, and thereby modulate insulin release. Biochemical studies by Aguilar-Bryan et al. (1995) indicated that SUR is a large membrane protein (140 to 170 kD).
By fluorescence in situ hybridization, Thomas et al. (1995) showed that the SUR gene maps to 11p15.1. Inagaki et al. (1995) determined that the BIR (600937) and SUR genes are clustered at 11p15.1, with the BIR gene immediately 3-prime of the SUR gene.
Inagaki et al. (1995) coexpressed SUR with BIR and observed reconstitution of an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to ATP, inhibited by sulfonylureas, and activated by diazoxide. The authors concluded that these pancreatic beta-cell potassium channels are a complex composed of at least 2 subunits: BIR and SUR.
Philipson and Steiner (1995) discussed the significance of the work on SUR. They compared the SUR protein with other members of the family of ATP-binding cassette proteins, including the multidrug resistance (MDR) proteins (e.g., 171050), which cause chemotherapeutic drug resistance when overexpressed, and the CFTR protein (602421), which is mutant in patients with cystic fibrosis (219700).
To test the effect of abolition of ATP hydrolysis on K-ATP channel activation by Mg-ADP and diazoxide in Xenopus oocytes, Gribble et al. (1997) mutated the critical lysine residues of the Walker A motifs in the first (K719A) and second (K1384M) nucleotide-binding domains (NBDs) of SUR1. The Walker A lysine of NBD1, but not of NBD2, was essential for activation. Both Walker A lysines were essential for potentiation by Mg-ADP. Mutant currents were more sensitive to inhibition by ATP than were wildtype currents. Metabolic inhibition led to activation of wildtype and K1384M currents, but not K719A or K719A/K1384M currents. These results suggested to the authors that an additional factor, besides ATP and ADP, regulates K-ATP channel activity.
Pocai et al. (2005) demonstrated that activation of K-ATP channels in the mediobasal hypothalamus is sufficient to lower blood glucose levels through inhibition of hepatic gluconeogenesis. The infusion of a K-ATP blocker within the mediobasal hypothalamus, or the surgical resection of the hepatic branch of the vagus nerve, negated the effects of central insulin (176730) and halved the effects of systemic insulin on hepatic glucose production in the mouse. Consistent with these results, mice lacking the SUR1 subunit of the K-ATP channel were resistant to the inhibitory action of insulin on gluconeogenesis. Pocai et al. (2005) concluded that activation of hypothalamic K-ATP channels normally restrains hepatic gluconeogenesis, and that any alteration within this central nervous system/liver circuit can contribute to diabetic hyperglycemia.
Familial Hyperinsulinemic Hypoglycemia 1
Familial hyperinsulinemic hypoglycemia (see HHF1, 256450), a disorder characterized by unregulated insulin secretion, was mapped to 11p15.1-p14 by linkage analysis (Glaser et al., 1994; Thomas et al., 1995; Fantes et al., 1995). The SUR protein was thought to be a likely candidate since it is a putative subunit of the beta-cell ATP-sensitive potassium channel, K(ATP), a modulator of insulin secretion. Thomas et al. (1995) detected 2 separate SUR gene splice site mutations that segregated with the disease phenotype in affected individuals from 9 different families (600509.0001 and 600509.0002). Both mutations resulted in aberrant processing of the RNA sequence and disruption of the putative second nucleotide-binding domain (NBF2) of the SUR protein.
In further studies on the role of the SUR nucleotide-binding folds in hyperinsulinemic hypoglycemia, Thomas et al. (1996) demonstrated that disruption of the first nucleotide-binding fold (NBF1) likewise leads to HHF (600509.0003-600509.0005). The data indicated that both nucleotide-binding-fold regions of the sulfonylurea receptor are required for normal regulation of beta-cell ATP-dependent potassium channel activity and insulin secretion.
Nestorowicz et al. (1996) screened a proband from each of 25 Ashkenazi Jewish families with hyperinsulinemic hypoglycemia for mutations in the SUR gene by SSCP analysis of genomic DNA and subsequent sequence analysis. They identified 2 common mutations. One mutation was a novel in-frame deletion of the codon for F1388 (600509.0006). This mutation creates a unique BseR1 restriction site in exon 34 allowing detection of noncarriers, homozygotes, and heterozygotes. The second mutation was a previously described G-to-A transition at position -9 of the 3-prime splice site of intron 32 (600509.0002). Extended haplotype analysis in the D11S1901-D11S1310 region revealed that these 2 mutations were associated with an H1 haplotype in 88% of patients studied, suggesting a founder effect. Nestorowicz et al. (1996) determined that F1388-deleted SUR is unable to form a functional K(ATP) channel with Kir6.2.
Nestorowicz et al. (1998) screened 45 familial hyperinsulinism probands of various ethnic origins for mutations in the SUR gene. SSCP and nucleotide sequence analyses of genomic DNA revealed a total of 17 novel and 3 previously described mutations. The novel mutations comprised 1 nonsense and 10 missense mutations, 2 deletions, 3 mutations in consensus splice site sequences, and an in-frame insertion of 6 nucleotides. One mutation occurred in the first nucleotide-binding domain (NBF1) of the SUR molecule and another 8 mutations were located in the second nucleotide-binding domain (NBF2), including 2 at highly conserved amino acid residues within the Walker A sequence motif. Most of the other mutations were distributed throughout the 3 putative transmembrane domains of the SUR protein. With the exception of the 3993-9G-A mutation (600509.0002), which was detected on 4.5% (4 of 88) disease chromosomes, allelic frequencies for the identified mutations varied between 1.1% and 2.3%. The clinical manifestations of familial hyperinsulinism in those patients homozygous for mutations in the SUR gene were described. In contrast to the allelic homogeneity of familial hyperinsulinism found in Ashkenazi Jewish patients (Nestorowicz et al., 1996), the findings of the wider study suggested that a large degree of allelic heterogeneity at the SUR locus exists in non-Ashkenazi patients.
From a morphologic standpoint, there are 2 types of histopathologic lesions underlying PHHI: a focal adenomatous hyperplasia of islet cells of the pancreas in approximately 30% of sporadic cases, and a diffuse form. In sporadic focal forms, specific losses of maternal alleles (LOH) of the imprinted chromosomal region 11p15, restricted to the hyperplastic area of the pancreas, were detected by de Lonlay et al. (1997). Similar mechanisms are observed in embryonal tumors and in the Beckwith-Wiedemann syndrome (BWS; 130650); the latter condition is also associated with neonatal but transient hyperinsulinism. The same chromosomal region, 11p15.1, includes the SUR gene and the KCNJ11 gene (600937), which code for the 2 subunits of the beta-cell K(+)-ATP channel. Recessive mutations in these genes cause recessive familial forms of PHHI, but appear not to be imprinted. Although the parental bias in loss of maternal alleles did not argue in favor of direct involvement of the SUR or KCNJ11 genes, the LOH may unmask a recessive mutation leading to persistent hyperinsulinism. Verkarre et al. (1998) reported somatic reduction to hemizygosity or homozygosity of a paternal SUR constitutional heterozygous mutation in 4 patients with a focal form of PHHI. Thus, this somatic event, which leads to both beta cell proliferation and hyperinsulinism, can be considered as the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous paternal mutation leading to a somatic recessive disorder.
Ryan et al. (1998) reported a similar situation in a non-Jewish hyperinsulinism patient with a single, paternally inherited SUR1 mutation. Glaser et al. (1999) proposed that some or all of the subjects with paternally inherited SUR1 mutations may have focal disease. In the 2 patients who underwent surgery, focal adenomatosis was documented. In one of these patients, tissue was available and reduction to homozygosity for the SUR1 mutation was also documented.
Glaser et al. (1999) examined pancreatic tissue from 3 patients with single paternal-allele mutations of the SUR1 gene and found focal beta-cell hyperplasia. DNA extracted from the focal lesions and adjacent normal pancreas revealed loss of the maternal chromosome 11p15, resulting in reduction to homozygosity for the SUR1 mutation, within the focal lesions only. Glaser et al. (1999) suggested that the combination of a paternally inherited SUR1 mutation along with somatic loss of the maternal allele of chromosome 11p may be the genetic etiology of most, if not all, cases of focal hyperinsulinism.
In 15 of 24 Finnish patients with hyperinsulinemic hypoglycemia (256450), Otonkoski et al. (1999) identified homozygosity or heterozygosity for a V187D mutation in the ABCC8 gene (600509.0013). The mutation was not found in 23 PHHI patients from outside Finland, suggestive of a founder effect. 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.
In 5 affected members of the 3-generation family ('family 1') with hyperinsulinemic hypoglycemia originally reported by Thornton et al. (1998), Thornton et al. (2003) identified heterozygosity for a 3-bp deletion in exon 34 of the ABCC8 gene (600509.0014).
In an infant of Spanish descent with hyperinsulinemic hypoglycemia, Tornovsky et al. (2004) identified a mutation in the promoter of the ABCC8 gene (600509.0015) on the paternal allele. 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.
Henwood et al. (2005) measured acute insulin responses (AIRs) to calcium, leucine, glucose, and tolbutamide in 22 infants with recessive ABCC8 or KCNJ11 mutations, 8 of whom had diffuse hyperinsulinism and 14 of whom had focal hyperinsulinism. Of the 24 total mutations, 7 showed evidence of residual K(ATP) channel function: 2 of the patients with partial defects were homozygous and 4 heterozygous for amino acid substitutions or insertions, and 1 was a compound heterozygote for 2 premature stop codons.
Goksel et al. (1998) found that a silent single-nucleotide polymorphism (SNP) in exon 31 of the SUR1 gene (AGG-AGA; arg1273 to arg) was strongly associated with insulin response to an oral glucose load in nondiabetic Mexican-American subjects. This observation prompted Reis et al. (2000) to investigate the possible association of this SNP with type II diabetes (NIDDM; see 125853) in French Caucasian subjects. They observed an increased frequency of the A allele in patients compared with controls. This association was stronger in the subgroup of patients who were diagnosed at age 45 years or younger. Unexpectedly, the G allele was strongly associated with arterial hypertension in obese diabetic subjects.
Laukkanen et al. (2004) investigated whether common polymorphisms in the ABCC8 and KCNJ11 genes were associated with increased risk of NIDDM in 490 subjects with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study. The 1273AGA allele of the ABCC8 gene was associated with a 2-fold risk of type II diabetes (odds ratio (OR), 2.00; 95% CI, 1.19-3.36; P = 0.009). This silent polymorphism was in linkage disequilibrium with 3 promoter polymorphisms, and they formed a high-risk haplotype having a 2-fold risk of type II diabetes (OR, 1.89; 95% CI, 1.09-3.27; P = 0.023). Subjects with both the high-risk haplotype of the ABCC8 gene and the 23K allele of the KCNJ11 gene (see E23K, 600937.0014) had a 6-fold risk for the conversion to diabetes compared with those without any of these risk genotypes (OR, 5.68; 95% CI, 1.75-18.32; P = 0.004). Laukkanen et al. (2004) concluded that polymorphisms of the ABCC8 gene predict the conversion from impaired glucose tolerance to NIDDM and that the effect of these polymorphisms on diabetes risk was additive with that of the E23K polymorphism of the KCNJ11 gene.
Meirhaeghe et al. (2001) described an association study between type II diabetes and response to sulfonylurea therapy and a polymorphism of the SUR1 gene: IVS16-3T-C. They investigated 122 subjects in 3 French cities: Lille (in the north), Strasbourg (in the east), and Toulouse (in the south). The genotypes of 1,250 controls were in Hardy-Weinberg equilibrium as follows: TT 29%, TC 50%, and CC 21%. The frequency of the -3C allele was 0.46 in controls. In NIDDM cases, the frequency of the C allele was 0.53. Subjects bearing at least one -3C allele and treated with sulfonylurea agents had fasting plasma triglyceride concentrations 35% lower than subjects who were TT homozygous, whereas no difference could be detected between genotypes in NIDDM subjects treated with other medications.
Lohmueller et al. (2003) performed a metaanalysis of genetic association studies to evaluate the contribution of common variants with a susceptibility to common disease. They concluded that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants. They analyzed 301 published studies covering 25 different reported associations. There was a large excess of studies replicating the first positive reports, inconsistent with the hypothesis of no true positive associations. This excess of replications could not be reasonably explained by publication bias and was concentrated among 11 of the 25 associations. The C/T SNP in exon 22 of the ABCC8 gene, which was first reported to show association of the T allele with type II diabetes (Inoue et al., 1996), was one of these. Another was association of a -3 T/C SNP in intron 24, with C showing association with type II diabetes, reported also by Inoue et al. (1996).
Giurgea et al. (2006) reported 3 patients with hyperinsulinemic hypoglycemia, all with paternally inherited SUR1 mutations. The first 2 patients both had 2 distinct foci of islet cell hyperplasia, and the third patient had a very large area of islet cell hyperplasia involving the major portion of the pancreas. In patients 1 and 2, haploinsufficiency for the maternal 11p15.5 region resulted from a somatic deletion specific for each of the focal lesions, as shown by the diversity of deletion breakpoints. In patient 3, an identical somatic maternal 11p15 deletion demonstrated by similar breakpoints was shown in 2 independent lesion samples, suggesting a very early event during pancreas embryogenesis. Giurgea et al. (2006) concluded that individual patients with focal hyperinsulinism may have more than 1 focal pancreatic lesion due to separate somatic maternal deletion of the 11p15 region. These patients and those with solitary focal lesions may follow the 2-hit model described by Knudson.
Pinney et al. (2008) identified 14 different dominantly inherited K(ATP) channel mutations in 16 unrelated families, 13 with mutations in the ABCC8 gene (see, e.g., 600509.0011) and 3 with mutations in the KCNJ11 gene (see, e.g., 600937.0020). Unlike recessive mutations, dominantly inherited K(ATP) mutant subunits trafficked normally to the plasma membrane when expressed in simian kidney cells; dominant mutations also resulted in different channel-gating defects, with dominant ABCC8 mutations diminishing channel responses to magnesium adenosine diphosphate or diazoxide and dominant KCNJ11 mutations impairing channel opening even in the absence of nucleotides. Pinney et al. (2008) concluded that there are distinctive features of dominant K(ATP) hyperinsulinism compared to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy.
Bellanne-Chantelot et al. (2010) analyzed the ABCC8 and KCNJ11 genes in 109 diazoxide-unresponsive patients with congenital hyperinsulinism and identified mutations in 89 (82%) of the probands. A total of 118 mutations were found, including 106 (90%) in ABCC8 and 12 (10%) in KCNJ11; 94 of the 118 were different mutations, and 41 had been previously reported. The 37 patients diagnosed with focal disease all had heterozygous mutations, whereas 30 (47%) of 64 patients known or suspected to have diffuse disease had homozygous or compound heterozygous mutations, 22 (34%) had a heterozygous mutation, and 12 (19%) had no mutation in the ABCC8 or KCNJ11 genes. The authors concluded that ABCC8 gene defects are the most important cause of diazoxide-unresponsive congenital hyperinsulinism.
In 29 patients with diazoxide-unresponsive hyperinsulinemic hypoglycemia, in whom direct sequencing revealed no mutation in the ABCC8 or KCNJ11 genes, or in whom a single recessively acting heterozygous ABCC8 mutation had been identified despite histologically confirmed diffuse pancreatic disease, Flanagan et al. (2012) used multiplex ligation-dependent probe amplification (MPLA) for ABCC8 dosage analysis and identified 3 different partial gene deletions (see, e.g., 600509.0027) in 4 patients (14%). Two of the patients, who had diffuse disease, also carried another ABCC8 mutation that had previously been detected by sequence analysis (see, e.g., 600509.0028), whereas the 2 patients with focal disease carried only the deletion in ABCC8. Pancreatic tissue was not available from the latter 2 patients for loss-of-heterozygosity studies.
In 5 patients with diazoxide-unresponsive focal hyperinsulinism in whom direct sequencing and MPLA dosage analysis failed to reveal a mutation in the ABCC8 or KCNJ11 genes, Flanagan et al. (2013) performed next-generation sequencing of the entire genomic region of ABCC8 and identified heterozygosity for a paternally inherited deep intronic splicing variant (1333-1013A-G; 600509.0029). The variant was also identified in homozygosity in 1 patient with diffuse hyperinsulinism. Chromosome 11 microsatellite analysis revealed a shared haplotype among the 6 patients, 4 of whom were from Ireland, suggesting that the variant represents a founder mutation in the Irish population.
Permanent Neonatal Diabetes Mellitus 3
In a 27-year-old man who had permanent neonatal diabetes (PNDM3; 618857) with severe developmental delay and generalized epileptiform activity on EEG, a triad referred to as DEND, Proks et al. (2006) identified heterozygosity for a de novo missense mutation (F132L; 600509.0016) in the ABCC8 gene. Functional studies showed that F132L markedly reduced the sensitivity of the K(ATP) channel to inhibition by MgATP, thereby increasing the whole-cell K(ATP) current; the authors noted that the functional consequence of the F132L mutation mirrors that of KCNJ11 mutations causing neonatal diabetes.
From a group of 73 patients with neonatal diabetes, Babenko et al. (2006) screened the ABCC8 gene in 34 who did not have alterations in chromosome 6q or mutations in the KCNJ11 or GCK (138079) genes. In 2 patients with permanent neonatal diabetes, they identified heterozygosity for a mutation (600509.0017 and 600509.0018, respectively). They also identified heterozygosity for 5 different mutations (see, e.g., 600509.0019-600509.0020) in 7 patients with transient neonatal diabetes (see 610374). Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had markedly higher activity than did wildtype channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. The mutation-positive fathers of 5 of the probands with transient neonatal diabetes developed type II diabetes mellitus (125853) in adulthood; Babenko et al. (2006) proposed that mutations of the ABCC8 gene may give rise to a monogenic form of type II diabetes with variable expression and age at onset. The authors noted that dominant mutations in ABCC8 accounted for 12% of cases of neonatal diabetes in the study group.
Ellard et al. (2007) studied a cohort of 59 patients with permanent neonatal diabetes who received a diagnosis before 6 months of age and who did not have a mutation in KCNJ11 (600937). ABCC8 gene mutations were identified in 16 of the 59 patients (see, e.g., 600509.0021-600509.0026), including 8 patients with heterozygous de novo mutations. The other 8 patients carried homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.
In a rat model of ischemic stroke (601367), Simard et al. (2006) found upregulation of Sur1 expression in ischemic neurons, astrocytes, and capillaries. Upregulation of Sur1 was linked to activation of the transcription factor Sp1 (189906) and was associated with expression of functional nonselective cation channels, which they called the NC(Ca-ATP) channel, but not K(ATP) channels. Treatment with low-dose glibenclamide, which blocks Sur1 and the NC(Ca-ATP) channel, reduced cerebral edema, infarct volume, and mortality by 50%. Simard et al. (2006) concluded that the NC(Ca-ATP) channel is involved in the development of cerebral edema and that targeting Sur1 may provide a new therapeutic approach to stroke.
In a child with hyperinsulinemic hypoglycemia (HHF1; 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.
In 2 sibs with hyperinsulinemic hypoglycemia (HHF1; 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.
In a boy with hyperinsulinemic hypoglycemia (HHF1; 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.
In 2 brothers with hyperinsulinemic hypoglycemia (HHF1; 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.
For discussion of the branch point mutation in the ABCC8 gene that was found in compound heterozygous state in patients with hyperinsulinemic hypoglycemia (HHF1; 256450) by Thomas et al. (1996), see 600509.0004.
In Ashkenazi Jewish families with hyperinsulinemic hypoglycemia (HHF1; 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.
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 (HHF1; 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).)
In a sporadic case of persistent hyperinsulinemic hypoglycemia of infancy (HHF1; 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.
In a sporadic case of persistent hyperinsulinemic hypoglycemia of infancy (HHF1; 256450) due to focal adenomatous hyperplasia, Verkarre et al. (1998) found a 4261C-T transition 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.
In 2 unrelated sporadic cases of persistent hyperinsulinemic hypoglycemia of infancy (HHF1; 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.
In affected members of a Finnish family with hyperinsulinemic hypoglycemia (HHF1; 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.
In a 4-year-old boy with leucine-sensitive hypoglycemia (LIH; 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.
In 15 of 24 Finnish patients with hyperinsulinemic hypoglycemia (HHF1; 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.
In 5 affected members of the 3-generation family (family 1) with hyperinsulinemic hypoglycemia (HHF1; 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 (600509.0006) mutation that causes recessive hyperinsulinism in Ashkenazi Jews.
In an infant of Spanish descent diagnosed 3 days postnatally with hyperinsulinemic hypoglycemia (HHF1; 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.
In a 27-year-old man who had permanent neonatal diabetes (PNDM3; 618857) with severe developmental delay and generalized epileptiform activity on EEG, 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. The authors considered the phenotype in this patient to be a case of DEND (developmental delay, epilepsy, and neonatal diabetes).
In a 5-year-old boy (family 12) with permanent neonatal diabetes mellitus (PNDM3; 618857) and neurologic features, Babenko et al. (2006) identified heterozygosity for a de novo leu213-to-arg (L213R) substitution. The patient's parents reported that he had motor and developmental delays, which were subsequently documented to include dyspraxia. He did not have seizures.
In a male patient (family 16) with permanent neonatal diabetes mellitus (PNDM3; 618857), Babenko et al. (2006) identified heterozygosity for a de novo ile1424-to-val (I1424V) substitution. This patient did not have abnormal cognitive function or development.
In a French girl (family 19) with transient neonatal diabetes mellitus (TNDM2; 610374) who had a recurrence of diabetes at age 6 and in affected members of an unrelated 5-generation French family (family 17) 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.
In a 2-year-old French boy (family 36) with transient neonatal diabetes mellitus (TNDM2; 610374) and in affected members of an unrelated 3-generation French family (family 16) 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.
In a patient from a cohort of 59 patients with permanent neonatal diabetes (PNDM3; 618857) who received a diagnosis before 6 months of age and who did not have a KCNJ11 mutation, Ellard et al. (2007) identified a 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.
In a patient with permanent neonatal diabetes mellitus (PNDM3; 618857), 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.
In a patient with permanent neonatal diabetes mellitus (PNDM3; 618857), 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.
In a patient with permanent neonatal diabetes mellitus (PNDM3; 618857), 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).
For discussion of the gly1401-to-arg (G1401R) mutation in the ABCC8 gene that was found in compound heterozygous state in a patient with permanent neonatal diabetes mellitus (PNDM3; 618857) by Ellard et al. (2007), see 600509.0024.
In an infant with permanent neonatal diabetes mellitus (PNDM3; 618857) 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.
In a male proband with diazoxide-unresponsive hyperinsulinemic hypoglycemia (HHF1; 256450), who had undergone near-total pancreatectomy and in whom a heterozygous 1-bp duplication (512dupT; 600509.0028) had previously been detected by Banerjee et al. (2011), Flanagan et al. (2012) used MPLA and found that the patient also carried a heterozygous deletion of exon 13 in the ABCC8 gene. His unaffected parents were each heterozygous for 1 of the mutations. Flanagan et al. (2012) also identified heterozygosity for the ABCC8 exon 13 deletion in another male proband who had undergone near-total pancreatectomy, histologic examination of which revealed normal pancreatic tissue, consistent with a focal lesion. The deletion was inherited from his unaffected father; pancreatic tissue was not available for loss-of-heterozygosity studies.
For discussion of the 1-bp duplication in the ABCC8 gene (512dupT) that was found in a patient with diazoxide-unresponsive hyperinsulinemic hypoglycemia (HHF1; 256450) by Banerjee et al. (2011) and Flanagan et al. (2012), see 600509.0027.
In 5 probands with diazoxide-unresponsive hypoglycemia due to focal hyperinsulinism (HHF1; 256450), Flanagan et al. (2013) identified heterozygosity for a 1333-1013A-G transition deep within intron 8 of the ABBC8 gene, creating a cryptic splice donor site that results in the inclusion of an out-of-frame 76-bp pseudoexon and premature termination. The mutation was inherited from the father in 4 of the patients; in the fifth patient, the mutation was not found in the mother but no DNA was available from the father. The variant was also identified in homozygosity in 1 patient with diffuse hyperinsulinism diagnosed on postmortem examination, and was present in heterozygosity in both parents. Chromosome 11 microsatellite analysis revealed a shared haplotype among the 6 patients, 4 of whom were from Ireland, suggesting that the variant represents a founder mutation in the Irish population.
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