Alternative titles; symbols
HGNC Approved Gene Symbol: ABCC9
SNOMEDCT: 239087008;
Cytogenetic location: 12p12.1 Genomic coordinates (GRCh38) : 12:21,797,389-21,941,426 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p12.1 | ?Atrial fibrillation, familial, 12 | 614050 | Autosomal dominant | 3 |
| Cardiomyopathy, dilated, 1O | 608569 | Autosomal dominant | 3 | |
| Hypertrichotic osteochondrodysplasia (Cantu syndrome) | 239850 | Autosomal dominant | 3 | |
| Intellectual disability and myopathy syndrome | 619719 | Autosomal recessive | 3 |
The ABCC9 gene encodes a regulatory sulfonylurea receptor (SUR2) that coassembles with pore-forming subunits KCNJ8 (600935 and KCNJ11 (600937) to form nucleotide-gated potassium channels (summary by Smeland et al., 2019).
ATP-sensitive potassium, or K(ATP), channels are characterized by inhibition of channel opening when the ATP concentration at the cytoplasmic cell surface is increased. Inagaki et al. (1996) noted that sulfonylureas, substances widely used as oral hypoglycemic agents in the treatment of noninsulin-dependent diabetes mellitus (NIDDM), have been shown to inhibit the activity of K(ATP) channels. A cDNA corresponding to SUR (600509), the high-affinity sulfonylurea receptor, was cloned by Aguilar-Bryan et al. (1995). Inagaki et al. (1995) showed that the pancreatic beta-cell K(ATP) channel consists of at least 2 subunits, BIR (600937) and SUR. An isoform of SUR, designated sulfonylurea receptor-2 (SUR2), was cloned by Inagaki et al. (1996) from a rat brain cDNA library. The 5,300-bp cDNA sequence encodes a polypeptide of 1,545 amino acids that shares 68% identity with SUR. Northern blot analysis showed that the tissue distribution of Sur2 is different from that of SUR.
Using rat Sur2 as probe, Chutkow et al. (1996) cloned SUR2 from a skeletal muscle cDNA library. Northern blot analysis detected 3 SUR2 transcripts of about 9.4, 7.6, and 5.6 kb, with the highest level of the longer transcript in heart and skeletal muscle. Little to no SUR2 expression was detected in other tissues examined. Chutkow et al. (1996) cloned 2 alternatively spliced mouse Sur2 cDNAs encoding deduced proteins of 1,512 and 1,547 amino acids, with calculated molecular masses of 170 and 174 kD, respectively. Mouse Sur2 has 13 transmembrane domains and intracellular Walker A and B ATP-binding domains. In contrast to the pattern of human SUR2 expression, mouse Sur2 was expressed ubiquitously as a 9.4-kb transcript. An 8.6-kb transcript was also detected at highest levels in skeletal muscle and heart and at lower levels in aorta and bladder. In situ hybridization of day-16.5 mouse embryos confirmed ubiquitous expression.
Smeland et al. (2019) noted that ABCC9 is alternatively spliced to yield 2 major isoforms, SUR2A and SUR2B.
By FISH, Chutkow et al. (1996) mapped the ABCC9 gene to chromosome 12p12.1.
Inagaki et al. (1996) found that coexpression of rat Sur2 and BIR in COS-1 cells reconstituted the properties of K(ATP) channels described in cardiac and skeletal muscle. However, the Sur2/BIR channel was less sensitive than the SUR/BIR channel both to ATP and to the sulfonylurea glibenclamide. The Sur2/BIR channel was activated by the cardiac K(ATP) channel openers cromakalim and pinacidil, but not by diazoxide. The authors noted that the affinity of Sur2 for sulfonylureas was 500 times lower than that of SUR.
Dilated Cardiomyopathy 10
Bienengraeber et al. (2004) identified 2 mutations in exon 38 of the ABCC9 gene that resulted in dilated cardiomyopathy (CMD1O; 608569). A male who was diagnosed at age 55 and died from heart failure at age 60 had a frameshift mutation (601439.0001). A female who was diagnosed at age 40 had an ala1513-to-thr substitution (601439.0002). Her father was diagnosed at age 54 and died at age 55 of heart failure. All 3 individuals had ventricular tachycardia and normal coronary angiography. The C terminus of SUR proteins contributes to K(ATP) channel trafficking, and the frameshift and missense SUR2A mutants, reconstituted with Kir6.2 (600937), had reduced expression in the plasma membrane; yet, mutant K(ATP) channel complexes formed functional channels with intact pore properties. Structural molecular dynamics stimulation showed that residues ala1513 and leu1524 flank the C-terminal beta-strand in close proximity to the signature Walker A motif, required for coordination of nucleotides in the catalytic pocket of ATP-binding cassette proteins. Replacement of ala1513 with a sterically larger and more hydrophilic threonine residue or truncation of the C terminus caused by the frameshift would disrupt folding of the C-terminal beta-strand. ATP-induced K(ATP) channel gating was aberrant in both channel mutants, suggesting that structural alterations induced by the mutations distorted ATP-dependent pore regulation.
Familial Atrial Fibrillation 12
In a 53-year-old white woman with paroxysmal atrial fibrillation (ATFB12; 614050), Olson et al. (2007) sequenced cardiac ion channel genes and identified a heterozygous mutation in the ABCC9 gene (T1547I; 601439.0003). The authors stated that subsequent targeted screening for the T1547I ABCC9 mutation in an additional 154 patients with diverse presentations of AF indicated that this specific genetic substitution is not common.
Hypertrichotic Osteochondrodysplasia
In 11 of 14 patients from 10 families with hypertrichotic osteochondrodysplasia (Cantu syndrome; 239850), van Bon et al. (2012) identified heterozygosity for 4 different missense mutations in the ABCC9 gene (601439.0004-601439.0007). Van Bon et al. (2012) noted that previously reported mutations in ABCC9 associated with CMD10 occur in an exon that is only transcribed in the isoform SUR2A, showing high cardiac muscle expression, which may explain why that phenotype remains restricted to the heart.
In 14 of 16 patients with Cantu syndrome, Harakalova et al. (2012) identified heterozygosity for 11 different missense mutations in the ABCC9 gene (see, e.g., 601439.0004, 601439.0005, and 601439.0008-601439.0011). Except for 1 mother-son pair, the mutation was shown to have arisen de novo in all of the patients for whom parental DNA was available. All of the mutations involved highly conserved regions of the protein, and none was present in more than 5,000 publicly available whole-exome sequences. Electrophysiologic studies demonstrated that the mutant channels reduce ATP-mediated potassium channel inhibition, resulting in channel opening.
Somatic Mutation in Cancer
Le Gallo et al. (2012) used whole-exome sequencing to comprehensively search for somatic mutations in 13 primary serous endometrial tumors (see 608089), and subsequently resequenced 18 genes that were mutated in more than 1 tumor and/or were components of an enriched functional grouping from 40 additional serous tumors. Le Gallo et al. (2012) identified a high frequency (6%) of somatic mutation in the ABCC9 gene.
Intellectual Disability And Myopathy Syndrome
In 6 patients from 2 unrelated families from the same region of Northern Norway with probable Finnish ancestry with intellectual disability and myopathy syndrome (IDMYS; 619719), Smeland et al. (2019) identified a homozygous splice site mutation in the ABCC9 gene (601439.0012). The mutation, which was found by targeted next-generation sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression assays in cells expressing the mutation showed about a 50% decrease in protein expression compared to controls, and complete loss of K(ATP) channel function, consistent with a loss of function. There was no evidence for a dominant-negative effect. The authors postulated that some of the phenotypic features may be due to disrupted function of the gene in striated muscle, smooth muscle, and the cerebral vasculature.
Smeland et al. (2019) found that homozygous mice with a nonsense mutation in exon 8 of the Abcc9 gene showed progressively decreased motor performance due to fatigability, although sensorimotor function was normal. Older mutant mice developed cardiac abnormalities, including impaired left ventricular function, dilated cardiomyopathy, and hypertension. No abnormalities were observed in cognitive and behavioral tests. CRISPR/Cas9-mediated knockdown of the abcc9 gene in zebrafish resulted in decreased overall movements and decreased total swimming distance compared to controls, but they moved for a similar time period. Mutant zebrafish developed systolic dysfunction, reduced cardiac output, enlarged heart size, and increased velocity of red blood cells (possible hypertension) compared to controls. They also showed hypotelorism as an isolated dysmorphic feature; hypotelorism was not observed in the mutant mice.
In a 55-year-old male with dilated cardiomyopathy with ventricular tachycardia (CMD1O; 608569), Bienengraeber et al. (2004) identified a complex mutation in the ABCC9 gene, a 3-bp deletion followed by a 4-bp insertion (4570-4572delTTAinsAAAT) causing a frameshift at leu1524 and introducing 4 anomalous terminal residues followed by a premature stop codon. The patient died at age 60 and had no family history of dilated cardiomyopathy. This mutation was not identified in 500 unrelated control individuals.
In a 40-year-old woman with dilated cardiomyopathy with ventricular tachycardia (CMD1O; 608569), Bienengraeber et al. (2004) identified a G-to-A transition at nucleotide 4537 of the ABCC9 gene, resulting in an alanine-to-threonine substitution at codon 1513 (A1513T). The patient's father died at age 55 of heart failure. The mutation was not present in the patient's mother, suggesting inheritance from the affected father. This mutation was not identified in 500 unrelated control individuals.
In a 53-year-old white woman with paroxysmal atrial fibrillation (ATFB12; 614050), Olson et al. (2007) identified heterozygosity for a 4640C-T transition in exon 38 of the ABCC9 gene, resulting in a thr1547-to-ile (T1547I) substitution at a conserved residue in the C terminus. The patient's relatives declined clinical or genetic evaluation, but the mutation was not found in 2,000 unrelated and predominantly white controls. Patch-clamp analysis demonstrated that the T1547I mutation compromised adenine nucleotide-dependent induction of K(ATP) current. Mutant SUR2A that was coexpressed with the Kir6.2 (KCNJ11; 600937) pore generated an aberrant channel that retained ATP-induced inhibition of potassium current, but showed a blunted response to ADP. In addition, Kir6.2-knockout mice developed AF in response to adrenergic stimulus, whereas wildtype mice remained in normal sinus rhythm.
In 3 unrelated patients with hypertrichotic osteochondrodysplasia (Cantu syndrome; 239850), van Bon et al. (2012) identified heterozygosity for a de novo 3460C-T transition in exon 27 of the ABCC9 gene, resulting in an arg1154-to-trp (R1154W) substitution at a highly conserved residue in the second type 1 transmembrane domain (TMD2). The mutation was not found in any of the over 5,000 publicly available exomes.
In a 5.5-year-old girl with Cantu syndrome, Harakalova et al. (2012) identified heterozygosity for a de novo R1154W mutation in ABCC9. The patient displayed the characteristic facies and generalized hypertrichosis of Cantu syndrome, associated with deep palmar/plantar creases, soft skin, a silvery shine to her hair, patent ductus arteriosus and foramen ovale, and a left ventricle that was at the upper limit of normal in size.
In 5 patients from 3 families with Cantu syndrome (239850), including a mother and 2 daughters originally reported by Grange et al. (2006), van Bon et al. (2012) identified heterozygosity for a 3461G-A transition in exon 27 of the ABCC9 gene, resulting in an arg1154-to-gln (R1154Q) substitution at a highly conserved residue in the second type 1 transmembrane domain (TMD2). The mutation was not found in any of the over 5,000 publicly available exomes.
In a 15-month-old boy and an unrelated 20-year-old woman with Cantu syndrome, as well as a 21-year-old female patient previously reported by Scurr et al. (2011), Harakalova et al. (2012) identified heterozygosity for the R1554Q mutation in ABCC9. Inside-out patch-clamp experiments in human embryonic kidney cells demonstrated that R1154Q mutant channels have reduced ATP sensitivity compared to wildtype.
In a 4.5-year-old girl with Cantu syndrome (239850), van Bon et al. (2012) identified heterozygosity for a de novo 3128G-A transition in the ABCC9 gene, resulting in a cys1043-to-tyr (C1043Y) substitution in the second type 1 transmembrane domain (TMD2). The mutation was not found in any of the over 5,000 publicly available exomes.
In a father and daughter with Cantu syndrome (239850), van Bon et al. (2012) identified heterozygosity for a 1433C-T transition in the ABCC9 gene, resulting in an ala478-to-val (A478V) substitution in the first type 1 transmembrane domain (TMD1). The mutation was not found in any of the over 5,000 publicly available exomes.
In a mother and son with Cantu syndrome (239850), Harakalova et al. (2012) identified heterozygosity for a 3347G-A transition in the ABCC9 gene, resulting in an arg1116-to-his (R1116H) substitution at a highly conserved residue in the second transmembrane domain. The mutation was not present in more than 5,000 publicly available whole-exome sequences. Inside-out patch-clamp experiments in human embryonic kidney cells demonstrated that R1116H mutant channels have reduced ATP sensitivity compared to wildtype.
In a 4-year-old boy with Cantu syndrome (239850), previously reported by Scurr et al. (2011), Harakalova et al. (2012) identified heterozygosity for a 3346C-T transition in the ABCC9 gene, resulting in an arg1116-to-cys (R1116C) substitution at a highly conserved residue in the second transmembrane domain. The mutation was not present in more than 5,000 publicly available whole-exome sequences.
In a 12-year-old girl with Cantu syndrome (239850), originally reported by Robertson et al. (1999), Harakalova et al. (2012) identified heterozygosity for a de novo 3058T-C transition in the ABCC9 gene, resulting in a ser1020-to-pro (S1020P) substitution at a highly conserved residue in the second transmembrane domain. The mutation was not present in more than 5,000 publicly available whole-exome sequences.
In a 15-year-old girl with Cantu syndrome (239850), previously reported by Scurr et al. (2011), Harakalova et al. (2012) identified heterozygosity for a 178C-T transition in the ABCC9 gene, resulting in a his60-to-tyr (H60Y) substitution at a highly conserved residue in transmembrane domain 0.
In 6 patients from 2 unrelated families from the same region of Northern Norway with probable Finnish ancestry with intellectual disability and myopathy syndrome (IDMYS; 619719), Smeland et al. (2019) identified a homozygous G-to-A transition (c.1320+1G-A, NM_020297.2) in the ABCC9 gene, resulting in a splicing defect and the in-frame deletion of exon 8 (Ala389_Gln440del) within the transmembrane 1 domain (TMD1). The mutation, which was found by targeted next-generation sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was present within a shared region of homozygosity. It was present in the heterozygous state in the gnomAD database with a frequency of 0.0007 in the Finnish population and 0.00004 among non-Finnish Europeans. It was absent in the Asian and African populations in gnomAD, and never observed in the homozygous state. In vitro functional expression assays in cells expressing the mutation showed about a 50% decrease in protein expression compared to controls, and complete loss of K(ATP) channel function, consistent with a loss of function. There was no evidence for a dominant-negative effect.
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van Bon, B. W. M., Gilissen, C., Grange, D. K., Hennekam, R. C. M., Kayserili, H., Engels, H., Reutter, H., Ostergaard, J. R., Morava, E., Tsiakas, K., Isidor, B., Le Merrer, M., and 9 others. Cantu syndrome is caused by mutations in ABCC9. Am. J. Hum. Genet. 90: 1094-1101, 2012. [PubMed: 22608503] [Full Text: https://doi.org/10.1016/j.ajhg.2012.04.014]