ABCMdb

ABCC8 p.Arg1420His

Predicted by SNAP2:	A: D (75%), C: D (66%), D: D (91%), E: D (85%), F: D (85%), G: D (85%), H: D (66%), I: D (85%), K: N (78%), L: D (85%), M: D (75%), N: D (71%), P: D (91%), Q: D (66%), S: D (71%), T: D (80%), V: D (80%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Nateglinide is Effective for Diabetes Mellitus wit... Clin Pediatr Endocrinol. 2012 Jul;21(3):45-52. doi: 10.1297/cpe.21.45. Epub 2012 Jul 25. Saito-Hakoda A, Yorifuji T, Kanno J, Kure S, Fujiwara I
Nateglinide is Effective for Diabetes Mellitus with Reactive Hypoglycemia in a Child with a Compound Heterozygous ABCC8 Mutation.
Clin Pediatr Endocrinol. 2012 Jul;21(3):45-52. doi: 10.1297/cpe.21.45. Epub 2012 Jul 25., [PMID:23926410]

Abstract [show]
ABCC8 encodes the sulfonylurea receptor 1 (SUR1) subunits of the beta-cell ATP-sensitive potassium (K-ATP) channel playing a critical role in the regulation of insulin secretion, and inactivating mutations in ABCC8 cause congenital hyperinsulinism. Recently, ABCC8 inactivating mutations were reported to be involved in the development of diabetes mellitus later in life. We report a girl who was born macrosomic with transient hypoglycemia and thereafter developed diabetes mellitus accompanied by severe reactive hypoglycemia at the age of 11 yr. An OGTT (oral glucose tolerance test) revealed hyperglycemia due to poor early insulin response and subsequent hypoglycemia due to delayed prolonged insulin secretion. Hypoglycemia was improved by the combination of nateglinide, which stimulates early insulin secretion, and an alpha-glucosidase inhibitor, voglibose. Sequencing of the ABCC8 identified a compound heterozygous mutation (R1420H/F591fs604X), suggesting that this mutation may alter regulation of insulin secretion with advancing age, leading to diabetes mellitus with reactive hypoglycemia from hyperinsulinism. Therefore, long-term follow-up and periodic OGTTs are important for early detection of insulin dysregulation in congenital hyperinsulinism patients carrying the ABCC8 mutation, even though hypoglycemia resolves spontaneously during infancy. Furthermore, nateglinide may be useful therapeutically in the treatment of not only diabetes mellitus but also reactive hypoglycemia.

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No. Sentence Comment
5 Sequencing of the ABCC8 identified a compound heterozygous mutation (R1420H/F591fs604X), suggesting that this mutation may alter regulation of insulin secretion with advancing age, leading to diabetes mellitus with reactive hypoglycemia from hyperinsulinism. Therefore, long-term follow-up and periodic OGTTs are important for early detection of insulin dysregulation in congenital hyperinsulinism patients carrying the ABCC8 mutation, even though hypoglycemia resolves spontaneously during infancy. Furthermore, nateglinide may be useful therapeutically in the treatment of not only diabetes mellitus but also reactive hypoglycemia. Login to comment
50 ABCC8 analysis identified a compound heterozygous mutation, c.4259G>A (p.R1420H; exon35) and c.1773delC (p.F591fs604X; exon12). Login to comment
53 Discussion The characteristic clinical course in our case is that a patient carrying a compound heterozygous ABCC8 mutation (R1420H/ F591fs604X) was born macrosomic with severe hypoglycemia in the neonatal period followed by development of diabetes mellitus accompanied by repeated reactive hypoglycemia in childhood. Login to comment
73 Thepatientwedescribedcarriedacompound heterozygous ABCC8 mutation, c4259G>A (R1420H; exon 35, paternal) and c1773 delC (F591fs604X; exon 12, maternal). Login to comment
77 The patient (indicated by the arrow) carried a compound heterozygous ABCC8 mutation, c4259G>A (p.R1420H; exon 35, paternal) and c1773 delC (p.F591fs604X; exon 12, maternal). Login to comment
80 Although the substituted amino acid was different and the mutation was compound heterozygous in our case, the R1420H mutation may also impair K-ATP channel activity. Login to comment

[hide] ABCC8 R1420H Loss-of-Function Variant in a Southwe... Diabetes. 2015 Dec;64(12):4322-32. doi: 10.2337/db15-0459. Epub 2015 Aug 5. Baier LJ, Muller YL, Remedi MS, Traurig M, Piaggi P, Wiessner G, Huang K, Stacy A, Kobes S, Krakoff J, Bennett PH, Nelson RG, Knowler WC, Hanson RL, Nichols CG, Bogardus C
ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes.
Diabetes. 2015 Dec;64(12):4322-32. doi: 10.2337/db15-0459. Epub 2015 Aug 5., [PMID:26246406]

Abstract [show]
Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the beta-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community. A R1420H variant in SUR1 (ABCC8) was identified in 3.3% of the population (N = 7,710). R1420H carriers had higher mean birth weights and a twofold increased risk for type 2 diabetes with a 7-year earlier onset age despite being leaner than noncarriers. One individual homozygous for R1420H was identified; retrospective review of his medical records was consistent with HHI and a diagnosis of diabetes at age 3.5 years. In vitro studies showed that the R1420H substitution decreases KATP channel activity. Identification of this loss-of-function variant in ABCC8 with a carrier frequency of 3.3% affects clinical care as homozygous inheritance and potential HHI will occur in 1/3,600 births in this American Indian population.

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No. Sentence Comment
0 Leslie J. Baier,1 Yunhua Li Muller,1 Maria Sara Remedi,2 Michael Traurig,1 Paolo Piaggi,1 Gregory Wiessner,1 Ke Huang,1 Alyssa Stacy,1 Sayuko Kobes,1 Jonathan Krakoff,1 Peter H. Bennett,1 Robert G. Nelson,1 William C. Knowler,1 Robert L. Hanson,1 Colin G. Nichols,2 and Clifton Bogardus1 ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes Diabetes 2015;64:4322-4332 | DOI: 10.2337/db15-0459 Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the b-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). Login to comment
2 A R1420H variant in SUR1 (ABCC8) was identified in 3.3% of the population (N = 7,710). Login to comment
3 R1420H carriers had higher mean birth weights and a twofold increased risk for type 2 diabetes with a 7-year earlier onset age despite being leaner than noncarriers. Login to comment
4 One individual homozygous for R1420H was identified; retrospective review of his medical records was consistent with HHI and a diagnosis of diabetes at age 3.5 years. Login to comment
5 In vitro studies showed that the R1420H substitution decreases KATP channel activity. Login to comment
51 For the six rare ABCC8 missense variants, samples that clustered as heterozygous or homozygous for the variant allele or as undetermined using TaqMan assays (clustering for the R1420H variant is shown in Supplementary Fig. 1) were directly sequenced to confirm the genotypes. Login to comment
62 Functional Analysis of the ABCC8 R1420H and R1420C Missense Mutations Site-directed mutagenesis (QuikChange; Stratagene, La Jolla, CA) of hamster ABCC8 cDNA cloned into pCMV6B was used to generate the R1420H and R1420C missense mutations. Login to comment
70 The other 6 missense variants (all in ABCC8: K1565E, R1420H, G1316Q, M801I, D691E, and S165L) are novel with mAFs of #0.03. Login to comment
71 Only the R1420H variant in ABCC8 is predicted to be damaging based on SIFT (29) and PolyPhen-2 (30) protein sequence analysis. Login to comment
74 After correction for multiple comparisons by the Bonferroni method across the 44 variants and three traits (significance threshold P # 0.0004), only the ABCC8 R1420H variant showed a significant association with birth weight (P = 0.0004) and adult BMI (P = 0.0001), where the H allele was associated with higher birth weight but lower BMI in adulthood. Login to comment
75 The type 2 diabetes association for R1420H in this sample was P = 0.04 and the odds ratio (OR) was 1.57 (95% CI 1.03-2.40) per copy of the H allele. Login to comment
80 When analyzed in all available DNA samples, the ABCC8 R1420H variant showed the strongest evidence for association with type 2 diabetes. Login to comment
81 R1420H carriers (i.e., heterozygotes) had twice the risk for type 2 diabetes as compared with individuals homozygous for R1420R (OR 2.02 [95% CI 1.45-2.82], P = 3.6 3 1025 ) (Table 2). Login to comment
82 The increased diabetes risk for R1420H carriers (3.3% of the population) was observed at all ages (Fig. 1A). Login to comment
83 The mean age of diabetes onset was, on average, earlier for R1420H carriers (45.0 years) compared with noncarriers (52.1 years), and the cumulative incidence of diabetes by age differed significantly between the two groups (hazard ratio 2.05, P = 1.1 3 1027 ) (Fig. 1B). Login to comment
84 Among the 7,528 individuals successfully genotyped for the ABCC8 R1420H variant, only one was homozygous (i.e., H1420H). Login to comment
87 Despite the increased diabetes risk, R1420H carriers had, on average, lower BMIs in adulthood prior to their development of type 2 diabetes (P = 2.5 3 1023 ) (Table 2). Login to comment
88 Analysis of the association with type 2 diabetes among subjects stratified by their maximum adult BMI at a nondiabetic exam showed an increase in the prevalence of type 2 diabetes among R1420H carriers at every level of BMI (Fig. 2). Login to comment
89 However, the younger age of type 2 diabetes onset observed in R1420H carriers could affect this BMI analysis (i.e., the last nondiabetic exam is more likely to occur at a younger age and, consequently, a lower BMI among R1420H carriers). Login to comment
91 In both the R1420H carriers and noncarriers, BMI was the highest around the time of diabetes diagnosis with lower values prior to diagnosis and at longer diabetes duration, which is a pattern that has been previously described in this population (31). Login to comment
92 However, the mean BMI was consistently lower in R1420H carriers at all times before and after diabetes diagnosis (P = 7 3 1024 ) (Fig. 3A). Login to comment
93 For comparison, analysis of maximum BMI stratified by age at maximum BMI from 4,210 subjects who did not have diabetes as of their last exam showed that R1420H carriers without diabetes also had lower BMIs as compared with similarly aged noncarriers without diabetes (P = 0.01) (Fig. 3B). Login to comment
94 The ABCC8 R1420H variant also had an association with birth weight (P = 1.5 3 1023 ) (Table 2), where newborns who carry R1420H were, on average, 170 g heavier than noncarriers. Login to comment
95 In a within-family analysis, the mean birth weight for offspring carrying R1420H was also higher than that of their siblings who do not carry the variant, adjusted for sex, gestational age, and maternal diabetes status during the pregnancy (N = 23 sibships, P = 0.01 for within-sibship difference in birth weight) (Fig. 4). Login to comment
96 In a sample of 298 full-heritage Pima Indian adults with normal glucose tolerance (8 carry R1420H) who had undergone detailed metabolic phenotyping in our Clinical Research Center, there was no association between R1420H and the acute insulin response to a 25-g IVGTT (P = 0.83), while there was a nominal association with rate of insulin-stimulated glucose uptake such that the R1420H carriers were more insulin sensitive (P = 0.03) (Supplementary Table 3). Login to comment
97 However, these data are potentially unreliable due to the small number of R1420H carriers. Login to comment
99 In these larger samples, there was no difference in HOMA-IR between R1420H carriers and noncarriers (P = 0.90, data not shown), but CIR was lower in the 118 R1420H carriers by 0.12 SD (P = 0.01). Login to comment
100 A lower CIR among R1420H carriers was observed across all age-groups (Fig. 5). Login to comment
101 The R1420H variant is a singleton and does not tag any of the other exonic variants detected in KCNJ11 or ABCC8 (Table 2) or tag any noncoding variant identified in our whole-genome sequence data from 335 Pima Indians (r2 ,0.2 with all other detected variants spanning chr11:17,406,795-17,498,449). Login to comment
102 Although the S165L variant also had a weak association with type 2 diabetes (OR 1.59 [95% CI 1.07-2.35], P = 0.02) (Table 2), conditional analysis showed that the signals from R1420H and S165L are likely to be independent (R1420H: conditional OR 2.04 [1.45-2.86], P = 3.7 3 1025 ; S165L: conditional OR 1.56 [1.05-2.04], P = 0.03). Login to comment
103 Therefore, the in vitro effects of the R1420H amino acid change on KATP channel activity were examined by measuring 86 Rb+ efflux across the plasma membrane of COSm6 cells cotransfected with KCNJ11 and either ABCC8 R1420R or ABCC8 R1420H. Login to comment
104 In addition to R1420H, a different substitution at the same amino acid (R1420C, rs28938469), which has previously been shown to decrease KATP channel (32,33), was also Table 1-Subjects from the Gila River Indian Community genotyped and analyzed for all missense variants N Males/females Age (years) Adult BMI (kg/m2 ) or birth weight (g) Type 2 diabetes With type 2 diabetes 2,549 982/1,567 46.5 6 14.6 38.7 6 8.6 Full-heritage Pima Indian 1,684 623/1,061 49.1 6 14.0 38.7 6 8.6 Non-full-heritage Pima Indian 865 359/506 41.2 6 14.1 38.7 6 8.7 Without type 2 diabetes 5,161 2,444/2,717 27.6 6 13.5 34.6 6 8.6 Full-heritage Pima Indian 1,941 930/1,011 32.1 6 14.6 36.0 6 8.5 Non-full-heritage Pima Indian 3,220 1,514/1,706 24.9 6 11.9 33.5 6 8.4 BMI Full-heritage Pima Indian 2,862 1,239/1,623 32.2 6 11.8 36.3 6 8.3 Non-full-heritage Pima Indian 3,056 1,367/1,689 27.3 6 10.5 34.0 6 8.4 Birth weight Full-heritage Pima Indian 988 439/549 - 3,468 6 523 Non-full-heritage Pima Indian 1,389 619/770 - 3,483 6 521 Metabolic studies (full-heritage Pima Indian) 298 207/119 26.3 6 6.2 33.4 6 7.4 Data are shown as n or mean 6 SD. Login to comment
107 However, when KATP-specific fluxes were activated by metabolic inhibition or diazoxide administration, 86 Rb+ effluxes were lower for both R1420H and R1420C KATP channels (Fig. 6). Login to comment
109 These data indicate that the R1420H amino acid change acts in a similar manner to the previously characterized R1420C substitution (32,33) to reduce KATP channel activity in intact cells, predicting that in vivo insulin hypersecretion will result in individuals carrying the R1420H variant. Login to comment
110 DISCUSSION In our population-based study of American Indians, we detected a R1420H loss-of-function variant in ABCC8. Login to comment
111 R1420H carriers had increased birth weights, suggestive of insulin oversecretion in utero, and a twofold increase in diabetes risk with a 7-year younger age of onset. Login to comment
114 The one individual homozygous for R1420H in our study had HHI and was diagnosed with diabetes at age 3.5 years, suggesting the potential for a profound phenotype when R1420H is inherited from both parents. Login to comment
115 Our observation of a 3.3% carrier rate among individuals living in the Gila River Indian Community, whose population is estimated to be about 14,000, suggests that 1/3,600 births in this community will be homozygous for R1420H. Login to comment
118 As DNA is not available on a population basis for most American Indian communities, it is unknown whether the ABCC8 R1420H variant also impacts other American Indian tribes. Login to comment
119 However, our recent screening of 2,576 individuals from the greater Phoenix area who have an American Indian heritage $50% but are not Pima Indian identified only two siblings heterozygous for the R1420H variant, suggesting that the variant may be rare in other Southwestern American Indian tribes. Login to comment
120 The R1420H variant also does not appear to occur at a detectable frequency in Table 2-Association of KCNJ11 and ABCC8 variants with type 2 diabetes, birth weight, and adult maximum BMI in American Indians from the Gila River Indian Community Diabetes (N = 7,710) Birth Weight (N = 2,377) Adult BMI* (N = 5,918) Gene Variant Freqߤ OR (95% CI) minor allele Pߥ B minor allele (g) P&#a7; B minor allele (log e ) P|| KCNJ11 rs5215 V337I 0.39 1.03 (0.94-1.12) 0.54 221.2 0.16 20.0001 0.98 KCNJ11 rs5219 E23K 0.39 1.04 (0.95-1.13) 0.43 218.4 0.22 0.002 0.72 ABCC8 chr11:17414594T.C K1565E 0.01 0.88 (0.56-1.36) 0.56 44.9 0.52 20.051 0.01 ABCC8 chr11:17417205C.T R1420H 0.017 2.02 (1.45-2.82) 3.6 3 10 25 169.1 1.5 3 10 23 20.049 2.5 3 10 23 ABCC8 rs757110 A1369S 0.38 1.03 (0.94-1.12) 0.56 215.5 0.35 0.002 0.60 ABCC8 chr11:17418781C.T G1316Q&#b6; 0.0001 1.04 (0.32-3.38) 0.94 - - 0.037 0.40 ABCC8 chr11:17435016G.T M801I 0.03 1.29 (0.98-1.71) 0.07 272.9 0.08 0.009 0.53 ABCC8 chr11:17449457T.A D691E&#b6; 0.001 0.42 (0.07-2.70) 0.36 - - 20.162 4.1 3 10 23 ABCC8 chr11:17485070G.A S165L 0.01 1.59 (1.07-2.35) 0.02 71.0 0.32 0.078 1.8 3 10 24 OR (95% CI) per copy of the minor allele. Login to comment
127 However, there is a report of a Japanese pedigree with three family members who carry the R1420H variant (43). Login to comment
129 The father, who was a R1420H heterozygote, was apparently healthy, but his cousin, also a heterozygote, had a history of hypoglycemia as an infant (43). Login to comment
130 It is not known whether individuals heterozygous for the R1420H variant in our study were hyperinsulinemic as infants; however, their increased birth weights are suggestive of insulin oversecretion in utero. Login to comment
131 Consistent with our observation of higher birth weights among R1420H carriers, increased birth weight has also been reported for newborns with other loss-of-function ABCC8 mutations (44-46). Login to comment
135 Despite being hyperinsulinemic as infants, some individuals with HHI (including the ABCC8 R1420H homozygous individual in this study) eventually develop diabetes. Login to comment
137 Transgenic mouse models of congenital hyperinsulinemia with a dominant-negative KATP channel mutation also progress to hypoinsulinemic hyperglycemia later in life either spontaneously or in response to a high-fat Figure 2-The prevalence of type 2 diabetes for R1420H carriers and noncarriers in relation to BMI. Login to comment
139 As a comparison of prevalence between R1420H and R1420R at each level of BMI, ORs (95% CI) are as follows: BMI <25 kg/m2 , 2.32 (0.73-7.32); BMI 25-30 kg/m2 , 2.45 (1.30-4.62); BMI >30-35 kg/m2 , 1.09 (0.552.14); BMI >35-40 kg/m2 , 1.88 (1.01-3.49); and BMI >40 kg/m2 , 1.04 (0.45-2.46). Login to comment
140 Figure 1-Type 2 diabetes status for R1420H carriers and noncarriers. Login to comment
143 Mean onset age was calculated from the parameters of the Weibull model for an individual born in 1940, and the mean age for all other covariates was 45.0 years for R1420H and 52.1 years for R1420R. Login to comment
149 Closure of the SUR1 KATP channel Figure 3-Comparison of mean BMI for R1420H carriers and noncarriers in relation to diabetes status and age. Login to comment
151 Mean BMI at all exams before and after diagnosis of diabetes in 2,458 individuals who eventually developed diabetes (117 R1420H carriers [the one H1420H was included with the heterozygote carriers] and 2,341 noncarriers). Login to comment
154 BMI is significantly lower in all exams from R1420H carriers (P = 7 3 1024 adjusted for age, sex, birth year, time category, and ancestry in a mixed model that accounts for sibship and repeated examinations within individuals). Login to comment
156 The maximum BMI by age among 4,210 subjects who did not have diabetes as of their last exam (106 R1420H carriers and 4,104 noncarriers). Login to comment
157 The number of R1420H carriers/noncarriers at each age category are 15-24 years (50/1,922), 25-34 years (26/1,042), 35-44 years (19/747), 45-54 years (8/259), and $55 years (3/134). Login to comment
158 R1420H carriers had a lower BMI compared with noncarriers (P = 0.01 adjusted for age, sex, birth year, and ancestry in a model that accounts for sibship). Login to comment
159 Figure 4-Mean birth weight for siblings discordant for the R1420H variant. Login to comment
162 The mean birth weight of siblings with R1420H genotype was higher than that of siblings with the R1420R genotype in 18 of 23 sibships. Login to comment
164 Figure 5-CIR for R1420H carriers and noncarriers grouped by their age at last nondiabetic OGTT. Login to comment
171 Our in vitro functional study showed that the R1420H substitution caused decreased KATP channel activity in response to metabolic inhibition or diazoxide administration. Login to comment
172 R1420H is positioned in the second nucleotide binding fold (NBF2) of the SUR1 protein where other amino acid substitutions have been identified including R1420C, which was previously shown to be associated with a sporadic case of persistent HHI (15,63) (note: R1420C is referred to as R1421C in [63]). Login to comment
175 While further studies are required, it seems likely that R1420H also may impair KATP channel activity by affecting adenine nucleotide binding in NBF2. Login to comment
176 Although the in vitro study shows that the R1420H variant affects KATP channel function, we did not detect statistical evidence of decreased insulin secretory function for the eight R1420H carriers whose insulin response was measured by an IVGTT. Login to comment
177 In addition to the small sample size, these data may be difficult to interpret because this Figure 6-Decreased KATP activity for SUR1 (ABCC8) channels harboring R1420H or R1420C mutations. Login to comment
178 Relative 86 Rb+ efflux is shown as a function of time under basal conditions, in the presence of metabolic inhibition (MI), in the presence of KATP channel opener diazoxide, and for both control cells expressing green fluorescent protein and cells expressing R1420R, R1420H, or R1420C channels. Login to comment
182 The rate at which insulin secretion declines from hyper- to hypoinsulinemia due to loss-of-function mutations in SUR1 is unknown and may be highly variable, and it is possible that these eight R1420H carriers were able to maintain their normal glucose tolerance into adulthood because they were leaner and more insulin sensitive (P = 1 3 1024 and P = 0.03, for percent body fat and insulin sensitivity, respectively) (Supplementary Table 3) and therefore were protected from the added b-cell stress needed to respond to greater degrees of obesity and insulin resistance. Login to comment
183 Further analysis using a surrogate measure of insulin secretion (CIR) in 3,961 individuals (including 118 R1420H carriers) provided modest evidence that the R1420H carriers, on average, may indeed have reduced insulin secretory function as compared with noncarriers at all ages between 15 and 45 years and older. Login to comment
185 For the R1420H variant, carriers had lower BMIs than noncarriers, even after stratifying subjects by diabetes status (Fig. 3). Login to comment
189 In summary, we report a loss-of-function ABCC8 R1420H variant with a high carrier rate (3.3%) in a Southwestern American Indian Community. Login to comment
190 R1420H carriers have increased birth weight presumably due to fetal hyperinsulinemia and a twofold increased risk of diabetes with a younger age of onset. Login to comment
191 As there is a high prevalence of R1420H heterozygotes in this community and R1420H homozygotes are potentially at risk for HHI, medical care providers should be aware of the increased risk of HHI in infants born to parents from this ethnic group. Login to comment