SNOMEDCT: 609581006; ORPHA: 99886; DO: 0060334;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.1 | Diabetes mellitus, transient neonatal 3 | 610582 | Autosomal dominant | 3 | KCNJ11 | 600937 |
A number sign (#) is used with this entry because of evidence that transient neonatal diabetes mellitus-3 (TNDM3) is caused by heterozygous mutation in the KCNJ11 gene (600937) on chromosome 11p15.
For a phenotypic description and a discussion of genetic heterogeneity of transient neonatal diabetes mellitus, see 601410.
Yorifuji et al. (2005) studied members of a 4-generation family with dominantly inherited diabetes mellitus observed in 3 generations. None of the patients in this family had permanent neonatal diabetes. The proband had transient neonatal diabetes, and his paternal grandfather had been diagnosed with diabetes at 3 years of age. The proband's paternal aunt at age 26 developed gestational diabetes, which was transient, but was diagnosed with adult-onset diabetes at age 28 years. The proband's father developed diabetes at age 22 years. None of the patients were obese, and none had autoantibodies or insulin resistance. Two of the patients were successfully treated with oral sulfonylurea alone.
In 4 affected members of a 4-generation Japanese family with dominantly inherited diabetes mellitus observed in 3 generations, Yorifuji et al. (2005) identified a cys42-to-arg mutation in the KCNJ11 gene (C42R; 600937.0012). Patch-clamp experiments using the mutated KCNJ11 showed that the mutation causes increased spontaneous open probability and reduced ATP sensitivity. The effect, however, was partially compensated by the reduction of functional ATP-sensitive potassium channel expression at the cell surface, which could account for the milder phenotype of the patients. The authors concluded that these results broadened the spectrum of diabetes phenotypes caused by mutations of KCNJ11 and suggested that mutations in this gene should be taken into consideration not only for permanent neonatal diabetes but also for other forms of diabetes with milder phenotypes and later onset.
In a 20-year-old woman with transient neonatal diabetes mellitus in whom diabetes remitted at age 29 months and recurred at age 7 years, Colombo et al. (2005) identified heterozygosity for a de novo missense mutation in the KCNJ11 gene (R201H; 600937.0002). Noting that there were no differences in terms of birth weight centile and time of onset of hyperglycemia between this patient and 14 individuals with permanent neonatal diabetes mellitus reported to carry the same mutation (see, e.g., Gloyn et al., 2004 and 618856), the authors suggested that this patient might be more insulin-sensitive than other individuals with the R201H mutation.
Gloyn et al. (2005) identified 3 novel heterozygous mutations (see, e.g., 600937.0017-600937.0018) in 3 of 11 probands with clinically defined TNDM who did not have chromosome 6q24 abnormalities (see 601410).
Edghill et al. (2007) noted that the majority of KCNJ11 mutations resulting in neonatal diabetes mellitus occur de novo. They found that germline mosaicism was indicated by pedigree analysis in 2 of 18 families in which neither parent was affected and in 1 of 12 additional parents tested for somatic mosaicism. Edghill et al. (2007) concluded that de novo KCNJ11 mutations can arise during gametogenesis or embryogenesis, thus increasing the risk of neonatal diabetes for subsequent sibs.
Of 31 Japanese patients with NDM, including 16 with TNDM and 15 with permanent NDM (see PNDM1, 606176), Suzuki et al. (2007) identified a 6q24 abnormality in 11, a KCNJ11 mutation in 9, and an ABCC8 (600509) mutation in 2. All of the patients with the 6q24 abnormality and 2 patients with a KCNJ11 mutation had TNDM. Seven patients with a KCNJ11 mutation and the 2 with an ABCC8 mutation had PNDM. Suzuki et al. (2007) concluded that the 6q abnormality and KCNJ11 mutations are major causes of NDM in Japanese.
Colombo, C., Delvecchio, M., Zecchino, C., Faienza, M. F., Cavallo, L., Barbetti, F., Early Onset Study Group of the Italian Society of Paediatric Endocrinology and Diabetology. Transient neonatal diabetes mellitus is associated with a recurrent (R201H) KCNJ11 (KIR6.2) mutation. (Letter) Diabetologia 48: 2439-2441, 2005. [PubMed: 16205880] [Full Text: https://doi.org/10.1007/s00125-005-1958-1]
Edghill, E. L., Gloyn, A. L., Goriely, A., Harries, L. W., Flanagan, S. E., Rankin, J., Hattersley, A. T., Ellard, S. Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. J. Clin. Endocr. Metab. 92: 1773-1777, 2007. [PubMed: 17327377] [Full Text: https://doi.org/10.1210/jc.2006-2817]
Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004. [PubMed: 15115830] [Full Text: https://doi.org/10.1056/NEJMoa032922]
Gloyn, A. L., Reimann, F., Girard, C., Edghill, E. L., Proks, P., Pearson, E. R., Temple, I. K., Mackay, D. J. G., Shield, J. P. H., Freedenberg, D., Noyes, K., Ellard, S., Ashcroft, F. M., Gribble, F. M., Hattersley, A. T. Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum. Molec. Genet. 14: 925-934, 2005. [PubMed: 15718250] [Full Text: https://doi.org/10.1093/hmg/ddi086]
Suzuki, S., Makita, Y., Mukai, T., Matsuo, K., Ueda, O., Fujieda, K. Molecular basis of neonatal diabetes in Japanese patients. J. Clin. Endocr. Metab. 92: 3979-3985, 2007. Note: Erratum: J. Clin. Endocr. Metab. 93: 153 only, 2008. [PubMed: 17635943] [Full Text: https://doi.org/10.1210/jc.2007-0486]
Yorifuji, T., Nagashima, K., Kurokawa, K., Kawai, M., Oishi, M., Akazawa, Y., Hosokawa, M., Yamada, Y., Inagaki, N., Nakahata, T. The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J. Clin. Endocr. Metab. 90: 3174-3178, 2005. [PubMed: 15784703] [Full Text: https://doi.org/10.1210/jc.2005-0096]