Activating Mutations in the KCNJ11 Gene Encoding the ATP-Sensitive K+ Channel Subunit Kir6.2 Are Rare in Clinically Defined Type 1 Diabetes Diagnosed Before 2 Years

Abstract

We have recently shown that permanent neonatal diabetes can be caused by activating mutations in KCNJ11 that encode the Kir6.2 subunit of the ␤-cell ATP-sensitive K ؉ channel. Some of these patients were diagnosed after 3 months of age and presented with ketoacidosis and marked hyperglycemia, which could have been diagnosed as type 1 diabetes. We hypothesized that KCNJ11 mutations could present clinically as type 1 diabetes. We screened the KCNJ11 gene for mutations in 77 U.K. type 1 diabetic subjects diagnosed under the age of 2 years. One patient was found to be heterozygous for the missense mutation R201C. She had low birth weight, was diagnosed at 5 weeks, and did not have a high risk predisposing HLA genotype. A novel variant, R176C, was identified in one diabetic subject but did not cosegregate with diabetes within the family. In conclusion, we have shown that heterozygous activating mutations in the KCNJ11 gene are a rare cause of clinically defined type 1 diabetes diagnosed before 2 years. Although activating KCNJ11 mutations are rare in patients diagnosed with type 1 diabetes, the identification of a KCNJ11 mutation may have important treatment implications. Diabetes 53: 2998 -3001, 2004 W e have recently shown that heterozygous mutations in the Kir6.2 (KCNJ11) gene, on chromosome 11p15.1, accounts for approximately one-third of cases of permanent neonatal diabetes mellitus (PNDM) (1). The gene encodes a subunit of the ␤-cell ATP-sensitive K ϩ channel (K ATP channel) known as the inwardly rectifying K ϩ channel (Kir6.2). The K ATP channel plays a critical role in coupling metabolism to membrane electrical events, which bring about closure of the K ATP channel and initiate insulin secretion. Activating mutations in KCNJ11 cause familial and sporadic PNDM by decreasing ␤-cell insulin secretion through reduced ATP sensitivity of the K ATP channel (1). Subjects presented with marked hyperglycemia and ketoacidosis at a mean age of 7 weeks (range 0 -26), with 15% presenting outside 3 months. We hypothesized that KCNJ11 activating mutations could present in young children with a clinical diagnosis of type 1 diabetes.The KCNJ11 gene, encoding Kir6.2, is located close to the large IDDM2 linkage peak (logarithm of odds [LOD] ϭ 4.28) at 11p15.5 seen in the combined analysis of the U.S. and the U.K. type 1 diabetes genome-wide scans (2). IDDM2 is primarily explained by the insulin gene variable number tandem repeat (INS VNTR) region, located upstream of the insulin gene. However, after allowing for the INS VNTR, the resulting LOD score for chromosome 11 in this region was still suggestive of linkage (LOD ϭ 2.53), and it was suggested by Cox et al. (2) that there could be a second type 1 diabetes locus in this region. A subset of families linked to KCNJ11 might explain this. A recent large study did not find any association with type 1 diabetes of the single nucleotide polymorphism E23K in KCNJ11 (3).Type 1 diabetes is defined by an absolute deficiency of insulin secretion (4). The most common form is immunemedia...

The identification of a R201H mutation in KCNJ11, which encodes Kir6.2, and successful transfer to sustained-release sulphonylurea therapy in a subject with neonatal diabetes: evidence for heterogeneity of beta cell function among carriers of the R201H mutation

“…Our data support earlier reports suggesting that mutations in Kir6.2 are usually found in patients diagnosed at <3 months of age [3,4] and that these mutations are uncommon in those aged >6 months [6]. Although the proband had other relatives who had diabetes, these individuals did not have the mutation, thus demonstrating heterogeneity of aetiology in this family.…”

Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype

“…2). Fourteen of these families have previously been reported [1,2,7,9,13,15]. The majority of probands with a KCNJ11 mutation were white (n=24), but mutations were also found in patients of the following ethnicities: Asian (n=2), black African (n=1), Hispanic (n=1), White/African American (n=1), Hispanic/Asian (n=1), Black African/White/ American Indian (n=1).…”

“…The mutations causing the full DEND syndrome have not been described in patients with isolated diabetes. It is interesting that three of nine (33%) patients with the R201C mutation have intermediate The results shown are medians, with the range given in brackets DEND [4,10,13,15], which is not seen in those with the R201H (0 of 20) mutation at the same residue. This has only become clear with larger numbers and is in keeping with the greater severity of mutation seen in vitro [23].…”

“…Massa et al suggest that aetiological classifications do not follow this definition and propose the study of patients diagnosed in the first year as a new subgroup of permanent diabetes mellitus of infancy (PDMI) [4]. Only two studies to date have investigated patients aged over 6 months at diagnosis [4,13], and the latter only looked at six patients diagnosed between the ages of 3 months and 1 year. More information is needed from large series of patients to determine the prevalence of KCNJ11 mutations in different age groups.…”

“…These patients had mutations not seen in patients with isolated diabetes. Only three of 16 probands with a mutation at residue R201 had neurological symptoms, and all three patients had the less common R201C mutation [1,4,6,7,9,10,13,15,16]. Some patients with the V59M mutation have permanent neonatal diabetes with developmental delay but no epilepsy (intermediate DEND [I-DEND] syndrome) [1,4,6,10], whereas others have no reported neurological features [1,4].…”