This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gloyn, A. L. Articles by Ellard, S. Search for Related Content PubMed PubMed Citation Articles by Gloyn, A. L. Articles by Ellard, S.

Permanent Neonatal Diabetes due to Paternal Germline Mosaicism for an Activating Mutation of the KCNJ11 Gene Encoding the Kir6.2 Subunit of the ß-Cell Potassium Adenosine Triphosphate Channel

Diabetes and Vascular Medicine (A.L.G., E.L.E., L.W.H., A.T.H., S.E.), Peninsula Medical School, Exeter EX2 5AX, United Kingdom; Department of Pediatrics (E.A.C., R.S.), Dalhousie University and IWK Health Centre, Halifax B3K 6R8, Canada; Department of Pediatrics (T.C.), Ste. Justine Hospital, Universite de Montreal, Montreal H3T 1C5, Canada; and Wessex Clinical Genetics Service and Division of Human Genetics (I.K.T.), Southampton University and Hospitals National Health Service Trust, Southampton SO16 5YA, United Kingdom

Address all correspondence and requests for reprints to: Dr. Sian Ellard, Molecular Genetics, Old Pathology Building, Royal Devon & Exeter Hospital, Barrack Road, Exeter EX2 5DW, United Kingdom. E-mail: s.ellard{at}exeter.ac.uk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
Activating mutations in the KCNJ11 gene encoding for the Kir6.2 subunit of the ß-cell ATP-sensitive potassium channel have recently been shown to be a common cause of permanent neonatal diabetes. In 80% of probands, these are isolated cases resulting from de novo mutations. We describe a family in which two affected paternal half-siblings were found to be heterozygous for the previously reported R201C mutation. Direct sequencing of leukocyte DNA showed that their clinically unaffected mothers and father were genotypically normal. Quantitative real-time PCR analysis of the father’s leukocyte DNA detected no trace of mutant DNA. These results are consistent with the father being a mosaic for the mutation, which is restricted to his germline. This is the first report of germline mosaicism in any form of monogenic diabetes. The high percentage of permanent neonatal diabetes cases due to de novo KCNJ11 mutations suggests that germline mosaicism may be common. The possibility of germline mosaicism should be considered when counseling recurrence risks for the parents of a child with an apparently de novo KCNJ11 activating mutation.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
ATP-SENSITIVE POTASSIUM (K_ATP) channels play a central role in glucose-stimulated insulin secretion from pancreatic ß-cells, with insulin secretion being initiated by channel closure and inhibited by channel opening (1). The ß-cell K_ATP channel is an octomeric complex of four pore-forming inwardly rectifying potassium channel subunits (Kir6.2) and four regulatory sulfonylurea receptor subunits (SUR1) (2). Both Kir6.2 and SUR1 are required for correct metabolic regulation of the channel, with ATP closing the channel by binding to Kir6.2, and Mg-nucleotides (MgADP and MgATP) stimulating channel activity by interaction with SUR1. Sulfonylureas stimulate insulin secretion in type 2 diabetes by binding to SUR1 and closing K_ATP channels by an ATP-independent mechanism (1).

Inactivating mutations in the KCNJ11 gene encoding the Kir6.2 subunit and the ABCC8 gene encoding the SUR1 subunit cause hyperinsulinemia of infancy (3, 4). It is characterized by the uncontrolled secretion of insulin despite hypoglycemia. In contrast, we have recently shown that heterozygous activating mutations in the KCNJ11 gene are a common cause (34%) of permanent neonatal diabetes (PNDM) (5). Functional studies of the common mutation, R201H, demonstrated that it caused diabetes by a reduction in sensitivity to ATP, which prevents the K_ATP channel from closing and therefore prevents insulin secretion (5). In our series a high proportion (80%) of subjects were the result of de novo mutations in the proband so they did not have affected parents (5). Here we report a family in which two affected paternal half-siblings were found to have a heterozygous-activating mutation (R201C) in the KCNJ11 gene due to a paternal germline mosaic mutation.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
These two Canadian paternal half-brothers of mixed British ancestry both have PNDM. Neither the parents nor three female siblings have diabetes. Neither mother had gestational diabetes. The mothers are unrelated and come from different regions of the country. Written informed consent was obtained from all participants. The pedigree is presented in Fig. 1.

View larger version (8K): [in this window] [in a new window]   FIG. 1. Family pedigree. Pedigree showing family with R201C mutation. Family relationships were confirmed by a panel of 10 microsatellites. Squares represent males, circles, females. Black squares represent the individuals with neonatal diabetes. Allele status is shown underneath individuals. N, No mutation; M, mutation; NA, not available for testing; P, proband, the first affected family member recruited to this study.

Case 1 (III:1), born at 37 wk gestation, was well at birth but had intrauterine growth retardation with a birth weight of 2100 g [<–2.5 SD score (SDS)] and length 47 cm (–1.7 SDS) but a normal head circumference (33.5 cm). At d 3 of life, diabetes was diagnosed based on glucosuria and hyperglycemia (glucose 16.3 mmol/liter) without ketoacidosis. The serum insulin level was undetectable at less than 3.0 mU/liter. Insulin therapy was initiated and at discharge 1 month later, he required insulin doses of 0.6–0.9 U/kg·d. Diabetes management in infancy was complicated by several episodes of severe hypoglycemia. He is now a teenager and has required insulin continuously since birth. He does not have dysmorphic features. Motor development and muscle strength are normal. He walked at age 12 months. Language skills were delayed with initial echolalic speech until age 4 yr. He has ongoing learning difficulties, with language and mathematical skills being 4–5 yr behind his chronological age. Social skills are also delayed.

Case 2

Case 2 (III:5), the younger half-brother, was born at 39 wk gestation with a birth weight of 2450 g (<–2.0 SDS) and a normal length and head circumference. He presented with weight loss noted first at 10 d of age. At 17 d he presented with dehydration and voracious appetite. Hyperglycemia (27.3 mmol/liter) and glucosuria led to the diagnosis of diabetes. There was no ketonuria and he has never had ketoacidosis. Abdominal ultrasound showed that a pancreas was present. The serum insulin level at diagnosis with a glucose of 21.6 mmol/liter was undetectable at less than 14 pmol/liter. Initial treatment was with sc insulin lyspro diluted to 10 U/ml, followed by a mixture of neutral protamine Hagedorn and lyspro insulin. At discharge at age 1 month, he was on 1.12 U/kg·d of insulin. With this he experienced large swings in his blood glucose but no severe hypoglycemia. He was switched to an insulin pump (continuous sc insulin infusion; Auto Control Medical, Mississauga, Ontario, Canada) at age 6 months of age. He has required insulin continuously from birth with recent doses ranging from 0.55 to 0.75 U/kg·d. He has no dysmorphic features, and his early psychomotor development has been normal. He has been treated for gastroesophageal reflux and three episodes of wheezing.

Molecular genetic analysis

Exclusion of chromosome 6q24 abnormalities. Linkage to the 6q24 region related to transient neonatal diabetes was excluded. There was no uniparental disomy of chromosome 6 or any duplication or methylation defect of 6q24 in either case, and the boys inherited different paternal alleles for the D6S1704, D6S310, and D6S355 microsatellites in the transient neonatal diabetes gene region on chromosome 6.

Direct sequence analysis of the KCNJ11 gene. The coding region and the intron-exon boundaries of the ATP-sensitive channel subunit Kir6.2 (KCNJ11) gene were amplified from leukocyte genomic DNA by the PCR as previously described (5). The products were sequenced by standard methods on an ABI 3100 (Applied Biosystems, Warrington, UK). Family relationships were confirmed using a panel of chromosome 11 microsatellite markers (4).

Real-time PCR quantification of the mutant allele in blood. Genomic DNA from leukocytes was amplified using a mutation-specific TaqMan approach. Genomic DNA from the proband who is heterozygous for the R201C mutation was used in serial dilution (250 pg to 20 ng) to produce standard curves for probe validation. Primer and probe sequences are given in Table 1. DNA mixtures of known composition (0–100% mutated sequence diluted in wild-type DNA) were also used to determine probe sensitivity and accuracy. All samples were tested in triplicate. The use of mutation-specific probes with common primers ensures equal amplification of alleles because detection is independent of the efficiency of the PCR. Reactions contained 10 µl TaqMan universal PCR master mix, no AmpErase, 1 µl Assays-by-Design (Applied Biosystems, Warrington, UK) probe and primer mix (corresponding to 18 µM each primer and 5 µM each probe), and 40 ng DNA in a total volume of 20 µl. Amplification conditions were a single cycle of 95 C for 10 min followed by 40 cycles of 95 C for 15 sec and 60 C for 1 min.

–CT

	Results

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
Mutation identification in KCNJ11 by direct sequence analysis

We identified a previously reported (5) heterozygous mutation (CGT>TGT, R201C) in the proband (III:1) and his affected paternal half-sibling (III:5). The missense mutation substituting cysteine for arginine at codon 201 (R201C) was not found in any of the clinically unaffected family members including the affected siblings’ father (Fig. 1). Family relationships were confirmed by microsatellite analysis for both children’s parents.

Quantification of mutant allele in DNA from blood

A real-time PCR quantification method was used to determine whether the mutant allele was present in the father’s blood at levels that could not be detected by direct sequencing. Mutation-specific probes were used to quantify the mutant allele levels relative to the wild-type allele levels in the father’s blood. Validation studies showed the assay to be accurate and quantitative over the range of 0.4–99% mutant DNA. We were unable to detect any trace of mutant DNA in the paternal blood sample. This approach has previously been shown to be sensitive enough to detect less than 0.1% of mutant sequence (7). From these results we concluded that the mutation is not present in the DNA extracted from father’s blood, even at a very low level. Quantification of the mutant allele in DNA from the father’s sperm was not possible because the father had undergone a vasectomy.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
We have identified a heterozygous missense mutation (R201C) in the KCNJ11 gene, which is likely to represent a paternal germline mutation. The mutation is found in two affected paternal-half-siblings but was not present in the siblings’ unaffected father’s leukocyte DNA, consistent with the father being a germline mosaic for this mutation. The inability to detect the mutation even at low levels in blood suggests that this mutation is probably restricted to the gonads. The mutation is likely to have occurred in a gamete precursor cell and may be present in a high percentage of the germ cells because the mutation has been transmitted to more than one child. We were unable to test this directly because the father had undergone a vasectomy, which prohibited analysis of his sperm. An alternate explanation is that there were two de novo mutations in the two siblings. Position 201 is susceptible to mutation due to the presence of a CpG dinucleotide, which is a hot spot for mutations in mammalian genes, but the chance of the same spontaneous mutation occurring in two siblings would be less than 1 in 1,000,000 and therefore highly unlikely. DNA from the three unaffected siblings was not available for molecular haplotyping to establish whether they had inherited the same paternal haplotype as their affected siblings.

Germline mosaicism has been reported in only a small number of autosomal dominant disorders including familial hypocalcemia (8), renal coloboma (9), Albright hereditary osteodystrophy (10), familial hypertrophic cardiomyopathy (11), and tuberous sclerosis (12).

Germline mutations have not previously been described in monogenic diabetes, and this may reflect the low frequency of de novo mutations reported. In the most common monogenic form of diabetes, maturity-onset diabetes of the young, de novo mutation accounts for less than 1% of cases (13, 14, 15, 16, 17, 18, 19, 20). The high frequency (80%) of de novo mutations described in the KCNJ11 gene (5) and the mosaicism rate for other autosomal disorders in the range of 6–19% (21) probably explains why the first case in monogenic diabetes occurs in a family with PNDM due to a heterozygous activating KCNJ11 mutation.

Mosaicism has important consequences for the interpretation of molecular diagnostic tests and for genetic counseling. Because the mutation is not present in the father’s blood, it is likely that the mutation is restricted to his gonadal germ cells; therefore, transmission to the offspring is in its complete form. The frequency of mosaic mutations can be underestimated because they often remain undetected during routine mutation analysis, and there may not be subsequent affected siblings to suggest an alternative to a de novo mutation in the affected index case. Given the high frequency (80%) of de novo mutations described in our earlier report (5), it is anticipated that mosaicism may be present in a significant number of de novo KCNJ11 cases. When counseling unaffected parents of a child with a de novo KCNJ11 mutation, the recurrence risk of a second child being affected may be in the region of 6–19% [based on other autosomal disorders (21)].

The mutated residue (R201) is of considerable functional importance. This residue is conserved among man, rat, mouse, and bullfrog and across 10 members of the Kir channel family, supporting a critical role for this residue in channel function. Functional studies have shown that mutation of this residue causes a reduction in ATP sensitivity, which is sufficient to prevent channel closure and insulin secretion (5, 22). This mutation has been reported previously along with the most common mutation (R201H) (5). The location of the residue in the channel is illustrated in Fig. 2.

View larger version (24K): [in this window] [in a new window]   FIG. 2. Schematic representation of the Kir6.2 channel membrane topology showing the position of the mutated residue R201.

We present the first report of germline mosaicism for a mutation in the KCNJ11 gene, which is also the first case of mosaicism described in monogenic diabetes. It is important to consider the possibility of germline mosaicism during counseling for recurrence risks in a situation in which a de novo mutation appears likely. Given the high percentage (80%) of de novo mutations, germline mosaic mutations could be common in PNDM caused by KCNJ11 mutations.

	Note Added in Proof

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
The authors note and acknowledge that, since the submission and acceptance of this manuscript, a report of maternal germline mosaicism for a mutation in the HNF1ß gene causing neonatal diabetes has been published by Yorifuji et al. (23).

	Acknowledgments

 
The authors thank the family for their cooperation with this study and Dr. David Robinson (Human Genetics Research Division, University of Southampton, Southampton, UK) for excluding chromosome 6q24 abnormalities.

	Footnotes

 
This work was supported in Exeter by grants from Wellcome Trust, Diabetes UK. A.T.H. is a Wellcome Trust Research Leave Clinical Fellow.

Abbreviations: Ct, Crossing point; K_ATP, ATP-sensitive potassium; PNDM, permanent neonatal diabetes; SDS, SD score; SUR1, sulfonylurea receptor subunit.

Received March 24, 2004.

Accepted May 13, 2004.

	References

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 

1. Gribble FM, Reimann F 2003 Sulphonylurea action revisited: the post-cloning era. Diabetologia 46:875–891[CrossRef][Medline]
2. Clement JP, Kunjilwar K, Gonzalez G, Schwanstecher M, Panten U, Aguilar-Bryan L, Bryan J 1997 Association and stoichiometry of K-ATP channel subunits. Neuron 18:827–838[CrossRef][Medline]
3. Thomas PM, Cote GJ, Wohilk N, Haddad B, Mathew PM, Rabel W, Aquilar-Bryan L, Gagel RF, Byran J 1995 Mutations in the sulphonylurea receptor and familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268:426–429[Abstract/Free Full Text]
4. Thomas PM, Yuyang Y, Lightner E 1996 Mutation of the pancreatic islet inward rectifier, Kir6.2, also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 5:1809–1812[Abstract/Free Full Text]
5. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JMCL, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JPH, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njølstad PR, Ashcroft FM, Hattersley AT2004 Activating mutations in the ATP-sensitive potassium channel subunit Kir6.2 gene are associated with permanent neonatal diabetes, developmental delay and epilepsy. N Engl J Med 350:1838–1845
6. Applied Biosystems 2001 User bulletin 2; 11–15
7. Maas F, Schaap N, Kolen S, Zoetbrood A, Buno I, Dolstra H, de Witte T, Schattenberg A, van de Wiel-van Kemenade E 2003 Quantification of donor and recipient hemopoietic cells by real-time PCR of single nucleotide polymorphisms. Leukemia 17:630–633[CrossRef][Medline]
8. Hendy GN, Minutti C, Canaff L, Pidasheva S, Yang B, Nouhi Z, Zimmerman D, Wei C, Cole DE 2003 Recurrent familial hypocalcemia due to germline mosaicism for an activating mutation of the calcium-sensing receptor gene. J Clin Endocrinol Metab 88:3674–3681[Abstract/Free Full Text]
9. Amiel J, Audollent S, Joly D, Dureau P, Salomon R, Tellier AL, Auge J, Bouissou F, Antignac C, Gubler MC, Eccles MR, Munnich A, Vekemans M, Lyonnet S, Attie-Bitach T 2000 PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism. Eur J Hum Genet 8:820–826[CrossRef][Medline]
10. Aldred MA, Bagshaw RJ, Macdermot K, Casson D, Murch SH, Walker-Smith JA, Trembath RC 2000 Germline mosaicism for a GNAS1 mutation and Albright hereditary osteodystrophy. J Med Genet 37:E35
11. Forissier JF, Richard P, Briault S, Ledeuil C, Dubourg O, Charbonnier B, Carrier L, Moraine C, Bonne G, Komajda M, Schwartz K, Hainque B 2000 First description of germline mosaicism in familial hypertrophic cardiomyopathy. J Med Genet 37:132–134[Abstract/Free Full Text]
12. Yates JR, van Bakel I, Sepp T, Payne SJ, Webb DW, Nevin NC, Green AJ 1997 Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis. Hum Mol Genet 6:2265–2269[Abstract/Free Full Text]
13. Massa O, Meschi F, Cuesta-Munoz A, Caumo A, Cerutti F, Toni S, Cherubini V, Guazzarotti L, Sulli N, Matschinsky FM, Lorini R, Iafusco D, Barbetti F 2001 High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetes (SIEDP). Diabetologia 44:898–905[CrossRef][Medline]
14. Glucksmann MA, Lehto M, Tayber O, Scotti S, Berkemeier L, Pulido C, Wu Y, Nir W-J, Fang L, Markel P, Munnelly KD, Goranson J, Orho M, Young BM, Whitacre JL, McMenimen C, Wantman M, Tuomi T, Warram J, Krolewski AS, Groop LC, Thomas JD 1997 Novel mutations and a mutational hotspot in the MODY3 gene. Diabetes 46:1081–1086[Abstract]
15. Hager J, Blanche H, Sun F, Vaxillaire NV, Poller W, Cohen D, Czernichow P, Velho G, Robert JJ, Cohen N, Froguel P 1994 Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique. Diabetes 43:730–733[Abstract]
16. Velho G, Blanche H, Vaxillaire M, Bellanne-Chantelot C, Pardini VC, Timsit J, Passa P, Robert JJ, Weber IT, Marotta D, Pilkis SJ, Lipkind GM, Bell GI, Froguel P 1997 Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia 40:217–224[CrossRef][Medline]
17. Tonooka N, Tomura H, Takahashi Y, Onigata K, Kikuchi N, Horikawa Y, Mori M, Takeda J 2002 High frequency of mutations in the HNF-1 gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance. Diabetologia 45:1709–1712[CrossRef][Medline]
18. Bingham C, Ellard S, Allen L, Bulman M, Shepherd M, Frayling T, Berry PJ, Clark PM, Lindner T, Bell GI, Ryffel GU, Nicholls AJ, Hattersley AT 2000 Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1 ß. Kidney Int 57:898–907[CrossRef][Medline]
19. Ellard S 2000 Hepatocyte nuclear factor 1 (HNF-1 ) mutations in maturity-onset diabetes of the young. Hum Mutat 16:377–385[CrossRef][Medline]
20. Gloyn AL 2003 Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. Hum Mutat 22:353–362[CrossRef][Medline]
21. Zlotogora J 1998 Germ line mosaicism. Hum Genet 102:381–386[CrossRef][Medline]
22. Ribalet B, John SA, Weiss JN 2003 Molecular basis for Kir6.2 channel inhibition by adenine nucleotides. Biophys J 84:266–276[Abstract/Free Full Text]
23. Yorifuji T, Kurokawa K, Mamada M, Imai T, Kawai M, Nishi Y, Shishido S, Hasegawa Y, Nakahata T 2004 Neonatal diabetes mellitus and neonatal polycystic, displastic kidneys: phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1ß gene due to germline mosaicism. J Clin Endocrinol Metab 89:2905–2908[Abstract/Free Full Text]

This article has been cited by other articles:

				M. Polak Neonatal Diabetes Mellitus: Insights for More Common Forms of Diabetes J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3774 - 3776. [Full Text] [PDF]

				E. L. Edghill, A. L. Gloyn, A. Goriely, L. W. Harries, S. E. Flanagan, J. Rankin, A. T. Hattersley, and S. Ellard Origin of de Novo KCNJ11 Mutations and Risk of Neonatal Diabetes for Subsequent Siblings J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1773 - 1777. [Abstract] [Full Text] [PDF]

				R. Masia, J. C. Koster, S. Tumini, F. Chiarelli, C. Colombo, C. G. Nichols, and F. Barbetti An ATP-Binding Mutation (G334D) in KCNJ11 Is Associated With a Sulfonylurea-Insensitive Form of Developmental Delay, Epilepsy, and Neonatal Diabetes Diabetes, February 1, 2007; 56(2): 328 - 336. [Abstract] [Full Text] [PDF]

				S. Mamanasiri, S. Yesil, A. M. Dumitrescu, X.-H. Liao, T. Demir, R. E. Weiss, and S. Refetoff Mosaicism of a Thyroid Hormone Receptor-{beta} Gene Mutation in Resistance to Thyroid Hormone J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3471 - 3477. [Abstract] [Full Text] [PDF]

				E. R. Pearson, I. Flechtner, P. R. Njolstad, M. T. Malecki, S. E. Flanagan, B. Larkin, F. M. Ashcroft, I. Klimes, E. Codner, V. Iotova, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N. Engl. J. Med., August 3, 2006; 355(5): 467 - 477. [Abstract] [Full Text] [PDF]

				A. S. Slingerland and A. T. Hattersley Activating Mutations in the Gene Encoding Kir6.2 Alter Fetal and Postnatal Growth and Also Cause Neonatal Diabetes J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2782 - 2788. [Abstract] [Full Text] [PDF]

				C.-W. Lin, Y.-W. Lin, F.-F. Yan, J. Casey, M. Kochhar, E. B. Pratt, and S.-L. Shyng Kir6.2 Mutations Associated With Neonatal Diabetes Reduce Expression of ATP-Sensitive K+ channels: Implications in Disease Mechanism and Sulfonylurea Therapy Diabetes, June 1, 2006; 55(6): 1738 - 1746. [Abstract] [Full Text] [PDF]

				E. L. Edghill, R. J. Dix, S. E. Flanagan, P. J. Bingley, A. T. Hattersley, S. Ellard, and K. M. Gillespie HLA Genotyping Supports a Nonautoimmune Etiology in Patients Diagnosed With Diabetes Under the Age of 6 Months Diabetes, June 1, 2006; 55(6): 1895 - 1898. [Abstract] [Full Text] [PDF]

				G Norbury and C J Norbury DNA analysis: what and when to request? Arch. Dis. Child., April 1, 2006; 91(4): 357 - 360. [Abstract] [Full Text] [PDF]

				C. E. Boklage Embryogenesis of chimeras, twins and anterior midline asymmetries Hum. Reprod., March 1, 2006; 21(3): 579 - 591. [Abstract] [Full Text] [PDF]

				J R Porter and T G Barrett Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and {beta} cell failure J. Med. Genet., December 1, 2005; 42(12): 893 - 902. [Abstract] [Full Text] [PDF]

				J. C. Koster, M. A. Permutt, and C. G. Nichols Diabetes and Insulin Secretion: The ATP-Sensitive K+ Channel (KATP) Connection Diabetes, November 1, 2005; 54(11): 3065 - 3072. [Abstract] [Full Text] [PDF]

				P. Proks, C. Girard, and F. M. Ashcroft Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP Hum. Mol. Genet., September 15, 2005; 14(18): 2717 - 2726. [Abstract] [Full Text] [PDF]

				A. T. Hattersley and F. M. Ashcroft Activating Mutations in Kir6.2 and Neonatal Diabetes: New Clinical Syndromes, New Scientific Insights, and New Therapy Diabetes, September 1, 2005; 54(9): 2503 - 2513. [Abstract] [Full Text] [PDF]

				L. Li, X. Geng, M. Yonkunas, A. Su, E. Densmore, P. Tang, and P. Drain Ligand-dependent Linkage of the ATP Site to Inhibition Gate Closure in the KATP Channel J. Gen. Physiol., August 29, 2005; 126(3): 285 - 299. [Abstract] [Full Text] [PDF]

				A. L. Gloyn, F. Reimann, C. Girard, E. L. Edghill, P. Proks, E. R. Pearson, I. K. Temple, D. J.G. Mackay, J. P.H. Shield, D. Freedenberg, et al. Relapsing diabetes can result from moderately activating mutations in KCNJ11 Hum. Mol. Genet., April 1, 2005; 14(7): 925 - 934. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gloyn, A. L. Articles by Ellard, S. Search for Related Content PubMed PubMed Citation Articles by Gloyn, A. L. Articles by Ellard, S.