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Molecular Basis of Neonatal Diabetes in Japanese Patients

Department of Pediatrics, Asahikawa Medical College, Asahikawa 078-8510, Japan

Address all correspondence and requests for reprints to: Kenji Fujieda, M.D., Ph.D., Department of Pediatrics, Asahikawa Medical College, 2-1-1-1 Midorigaoka Higashi, Asahikawa 078-8510, Japan. E-mail: ken-fuji{at}asahikawa-med.ac.jp.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Neonatal diabetes mellitus (NDM) is classified clinically into a transient form (TNDM), in which insulin secretion recovers within several months, and a permanent form (PNDM), requiring lifelong medication. However, these conditions are genetically heterogeneous.

Objective: Our objective was to evaluate the contribution of the responsible gene and delineate their clinical characteristics.

Patients and Methods: The chromosome 6q24 abnormality and KCNJ11 and ABCC8 mutations were analyzed in 31 Japanese patients (16 with TNDM and 15 with PNDM). Moreover, FOXP3 and IPF1 mutations were analyzed in a patient with immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome and with pancreatic agenesis, respectively.

Results: A molecular basis for NDM was found in 23 patients: 6q24 in eleven, KCNJ11 in nine, ABCC8 in two, and FOXP3 in one. All the patients with the 6q24 abnormality and two patients with the KCNJ11 mutation proved to be TNDM. Five mutations were novel: two (p.A174G and p.C166Y) in KCNJ11, two (p.A90V and p.N1122D) in ABCC8, and one (p.P367L) in FOXP3. Comparing the 6q24 abnormality and KCNJ11 mutation, there were some significant clinical differences: the earlier onset of diabetes, the lower frequency of diabetic ketoacidosis at onset, and the higher proportion of the patients with macroglossia at initial presentation in the patients with 6q24 abnormality. In contrast, two patients with the KCNJ11 mutations manifested epilepsy and developmental delay.

Conclusions: Both the 6q24 abnormality and KCNJ11 mutation are major causes of NDM in Japanese patients. Clinical differences between them could provide important insight into the decision of which gene to analyze in affected patients first.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
NEONATAL DIABETES MELLITUS (NDM) is a rare disorder, with a reported incidence of one per 400,000–500,000 births, and hyperglycemia develops in the first 3 months of life in most cases (1). NDM is classified into two categories clinically. One is transient NDM (TNDM), in which insulin secretion is spontaneously recovered by several months of age but the condition sometimes recurs later, and the other is permanent NDM (PNDM), requiring lifelong medication (1). Recent molecular analysis of NDM identified 11 genetic abnormalities: chromosome 6q24, KCNJ11, ABCC8, FOXP3, GCK, IPF1, PTF1A, EIF2AK3, GLUT2, HNF1ß, and GLIS3 (2, 3, 4, 5, 6, 7). Of these, imprinting defects on chromosome 6q24 (7, 8, 9) and the KCNJ11 mutation (10, 11, 12) have been recognized as the major causes of TNDM and PNDM, respectively, in Caucasians. In addition, the ABCC8 heterozygous activating mutation has recently been reported to account for 12% of cases (5).

Overexpression of one or both imprinting genes (ZAC and HYMAI) at 6q24 displaying paternal expression has been identified as a cause of TNDM (13, 14, 15).

Both the inward-rectifier Kir6.2 encoded by KCNJ11 and sulfonylurea receptor SUR1 encoded by ABCC8 comprise the pancreatic ß-cell ATP-sensitive K⁺ channel. These are crucial for the regulation of glucose-induced insulin secretion (16). KCNJ11 and ABCC8 mutations are responsible for not only PNDM and TNDM but also developmental delay, epilepsy, and neonatal diabetes (DEND syndrome) (4, 5, 6, 10). This is believed to be because both of them are also expressed together in brain (17). Most of the patients with these mutations are reported to be well controlled with sulfonylurea (5, 18, 19). Thus, it is important clinically to determine the etiology of NDM.

To evaluate the contribution of the major responsible genes for the clinical course of NDM in Japanese patients, we screened for the 6q24 abnormality and the KCNJ11 and ABCC8 mutations in 31 Japanese patients with NDM. In addition, we analyzed the clinical features among each cause to delineate their clinical characteristics. Furthermore, FOXP3 and IPF1 mutations were analyzed in a patient with immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome and a patient with pancreatic agenesis, respectively.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

The patients we studied were 31 Japanese patients with NDM, who had exhibited a continuous hyperglycemia at median 37 d of age (range, 0–115 d). TNDM was defined as neonatal diabetes leading to a euglycemic state without medication later, and PNDM was defined as NDM other than TNDM. The patients were recruited on a voluntary basis through a network of pediatricians all over Japan. The study was approved by the local ethics committees, and informed consent was obtained from all patients and/or their parents for molecular analysis.

Genetic study

Genomic DNA was extracted from blood samples of the patients and their parents. To test for paternal uniparental disomy of chromosome 6 [pUPD(6)], the DNA samples were analyzed by using polymorphic microsatellite markers from the ABI Prism Linkage Mapping Set version 2 (Applied Biosystems, Foster City, CA). PCR products were electrophoresed by the ABI Prism 310 Genetic Analyzer (Applied Biosystems) and analyzed using the GeneScan and customized Genotyper software packages (Applied Biosystem). If the patients did not have pUPD(6), the detailed analysis of a paternal duplication of the 6q24 was performed with six newly developed primer sets for microsatellite markers (the author will provide greater details upon request). Methylation patterns were also analyzed by a methylation-sensitive PCR method according to the method of Kamiya et al. (20)

DNA samples from subjects were screened for the mutation of KCNJ11 (21), FOXP3 (22), and IPF1 (23) by direct sequencing, using published PCR primer sequences and conditions. ABCC8 analysis was performed with a modified method of the one described by Nestorowicz et al. (24) (the author will provide greater details upon request). To ascertain the presence or absence of mutations, DNA samples of 96 normal Japanese subjects were analyzed.

Clinical study

All referring clinicians were asked to complete a questionnaire regarding the birth history, clinical features at the diagnosis of diabetes, blood test results, and follow-up data of each patient. The term small for gestational age (SGA) is defined as a neonate whose birth weight or birth length is 2 SD below the mean (–2 SD) for the infant’s gestational age (25), based on data derived from a Japanese population (26).

The differences in clinical features between the patients with the 6q24 abnormality and the patients with the other causes were tested using the Student’s t test or Welch t test for quantitative variables and a ² test or Fisher’s exact probability test for qualitative variables. Because the distribution of gestational age was not Gaussian in the study population, the nonparametric Mann-Whitney U test was used to compare items between these groups. Results are reported as the means ± SD or as medians and ranges for continuous variables and as percentages for qualitative variables. P values of <0.05 were considered statistically significant.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Genetic study

We identified a molecular basis for neonatal diabetes in 23 of 31 patients: 6q24 abnormalities in 11 (35%), KCNJ11 mutations in nine (29%), ABCC8 mutations in two (6%), and FOXP3 mutation in one (3%) (Table 1 and Fig. 1A).

View larger version (31K): [in this window] [in a new window]   FIG. 1. Molecular and clinical epidemiology of Japanese patients with neonatal diabetes. The total number of patients was 31. A, Proportion of each molecular cause of neonatal diabetes. Italic characters indicate novel mutations. *, Classification of diabetes of two patients with R201H in the KCNJ11 mutation, and the patient with N1122D in the ABCC8 mutation may remain undetermined because of the short follow-up period. B, Proportion of TNDM and PNDM in neonatal diabetes. The number of TNDM and PNDM was 16 and 15, respectively. C, Proportion of each molecular cause of TNDM. D, Proportion of each molecular cause of PNDM.

Sequence analysis of ABCC8 identified two novel heterozygous missense mutations. The novel mutations were the substitution of alanine by valine at codon 90 (c.269C>T, p.A90V) and the substitution of asparagine by aspartate at codon 1122 (c.3364A>G, p.N1122D). No ABCC8 mutation was identified in both parents of any patient.

Patient 23, diagnosed as IPEX, had a novel hemizygous missense mutation in FOXP3, which was the substitution of phenylalanine by leucine at codon 367 (c.1099T>C, p.F367L).

Patient 27, with pancreatic agenesis, had no IPF1 mutation.

All of these mutations were not identified in the 96 normal control subjects.

Clinical study

Prevalence of TNDM and PNDM for each etiological cause of neonatal diabetes. The overall proportion of TNDM and PNDM in the 31 Japanese patients with NDM was 52% (16 of 31) and 48% (15 of 31), respectively (Fig. 1B). In TNDM, the proportion of the patients with 6q24 abnormalities and with the KCNJ11 mutation was 69% (11 of 16) and 13% (two of 16), respectively (Fig. 1C). All of the patients with 6q24 abnormalities presented with TNDM only. The proportion of the KCNJ11 mutation and ABCC8 mutation in PNDM was 47% (seven of 15) and 13% (two of 15), respectively (Fig. 1D). The proportion of TNDM and PNDM in KCNJ11 mutation was 22% (two of nine) and 78% (seven of nine), respectively.

Clinical characteristics for each cause of neonatal diabetes (Table 2)

Birth history. The NDM patients with an identified genetic cause had a lower mean birth weight compared with the average Japanese baby with correction for gestational age (26): 6q24, 1978 (718–2852) g, –1.5 SD (–3.0 to 0); KCNJ11, 2430 (1934–3028) g, –1.6 SD (–2.6 to –0.4); ABCC8, 2433 (2396–2470) g, –1.6 SD (–2.1 to –1.1); FOXP3, 1728 g, –3.1 SD. Over half of them were SGA.

Two patients with the ABCC8 mutation were diagnosed with diabetes mellitus at a median of 45 d of age. They exhibited hyperglycemia, leading to fever and dehydration in the patient with the A90V mutation and severe DKA, resulting in seizure in the patient with the N1122D mutation.

The patient diagnosed as IPEX manifested hyperglycemia leading to DKA at 8 d of age.

Clinical course

All the patients with the 6q24 abnormality recovered from diabetes mellitus, with a mean recovery age of 53 d (median, 51 d; range, 16–246 d) (Table 1). Almost all of patients were treated with insulin until remission. However, patient 10 recovered without any antidiabetic medication at 35 d of age (Table 1). In the patients with the KCNJ11 mutation, two patients with the R50Q and A174G mutations recovered from diabetes. Both of them exhibited normalized blood glucose at 307 d of age. However, recurrence of diabetes mellitus was noted in two TNDM patients with paternal 6q24 duplication (patient 11) and with the A174G mutation of KCNJ11 (patient 13). They relapsed at 10 and 3 yr of age, respectively, and have been subsequently treated with insulin.

The patients with R50G, C166Y, R201C, or R201H in the KCNJ11 and A90V mutations or N1122D in the ABCC8 mutation have been treated with insulin since diagnosis of diabetes.

The patient diagnosed as IPEX with a P367L mutation in FOXP3 was born with severe SGA at 38 wk gestation. He presented poor sucking and failure to thrive at 8 d of age. He was diagnosed as having diabetes mellitus based on an elevated blood glucose of 1352 mg/dl (74.5 mmol/liter), and insulin treatment was begun. Thereafter, he manifested intractable diarrhea and eczema, liver dysfunction with hyperammoniemia requiring exchange transfusion, thrombocytopenia, and sepsis. At 14 wk of age, he suffered from acute renal failure resulting in congestive heart failure and pulmonary edema. Although he underwent peritoneal dialysis continuously, he finally died at 16 wk of age with a progressively deteriorating course.

Complications such as developmental delay, epilepsy, and dysmorphic features. Two patients with the KCNJ11 mutation (patient 19 with R50G and patient 20 with C166Y) had severe developmental problems, indicating DEND syndrome. Patient 19 with R50G could not stand without support and did not speak any words at 8 yr of age and had been diagnosed with tonic spasms at 5 months of age. The patient with C166Y had also profound developmental delay and had been diagnosed with tonic spasms at 7 months of age. The patients with the ABCC8 mutation had no developmental delay. One patient with the 6q24 abnormality and one patient with unknown cause were born as extremely immature and extremely low-birth-weight infants with perinatal asphyxia, resulting in subsequent developmental delay (Table 1). Four patients with unknown cause had developmental delay of unknown origin, and two of them exhibited DEND syndrome (Table 2).

In terms of dysmorphic features, macroglossia at diagnosis was noticed in five of 11 patients (45%) with the 6q24 abnormality and two of eight (25%) with unknown cause. None of the patients with the KCNJ11 mutation had macroglossia. Patient 7 with pUPD(6) displayed a prominent forehead at the diagnosis of diabetes. Patient 20 (C166Y in KCNJ11) with the DEND syndrome had a down-turned mouth, bilateral ptosis, a prominent forehead, and arthrogryposis. Patient 19 with R50G in KCNJ11 causing the DEND syndrome had arthrogryposis but no dysmorphic face signs.

None of the patients with the ABCC8 or FOXP3 mutation had dysmorphic features.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The understanding of the molecular basis for NDM has become greatly advanced. At least 11 genetic abnormalities, which are responsible for either insulin secretion or the development of pancreas, have been identified.

In the present study, we have identified a molecular defect in 74% of Japanese patients. Of these, the 6q24 abnormality was found in 34%, the KCNJ11 mutation in 24%, the ABCC8 mutation in 6%, and the FOXP3 mutation in 3%. Thus, these results indicate that both the 6q24 abnormality and the KCNJ11 mutation are prevalent causes in Japanese NDM patients, as has been shown in Caucasians (5, 6, 7, 9, 11, 12). Five novel mutations were identified: two in KCNJ11, two in ABCC8, and one in FOXP3. Although we have not performed a functional study for them, there is strong evidence that they are pathogenic because all of them were de novo mutations, all these residues were conserved among other species, and none of these mutations was found in normal subjects.

The birth year of 25 patients was between 2000 and 2005 (Table 1). During these years, 7 million babies were born in Japan. Thus, the prevalence of NDM in Japanese is estimated to be at least greater than approximately one in 300,000 births. However, in our study, the patients with NDM may be underestimated because the patients were recruited on a voluntary basis rather than a population basis, and all of them were diagnosed within 4 months of age. Now, NDM may be defined as hyperglycemia that develops in the 6 months of age based on human leukocyte antigen data (27). Actually, the KCNJ11 or ABCC8 mutations occurred in the patients over 6 months of age (5, 10). Thus, the incidence of NDM in Japanese could be higher than in Caucasians (1). Another limitation of this study was the fact that the age of some patients was too young to determine whether they would go to remission in future because some patients with TNDM have remitted after 1 yr of age (28, 29). This suggests that the proportion of TNDM could be underestimated.

The majority of clinically diagnosed TNDM patients displayed 6q24 abnormalities. One TNDM patient with the 6q24 abnormality relapsed into diabetes at the age of 10 yr.

The mutation of the R201 residue of KCNJ11 was identified in five of nine patients, suggesting that this is a hot spot in Japanese patients with NDM. KCNJ11 activating mutation was identified in patients who were clinically diagnosed as TNDM, PNDM, and DEND syndrome. The severity of the phenotype is generally considered to reflect the severity of channel dysfunction (6, 28, 30). A definite genotype-phenotype correlation was observed in a large cohort (10). However, exceptional cases have been reported. The patients with R201H usually manifest PNDM. However, one patient was reported to manifest TNDM (31). Similarly, our patient with the R50Q mutation exhibited TNDM, which is different from the previous report about the patient exhibiting PNDM with R50Q (10). Thus, these findings suggest that the same mutation in KCNJ11 does not always manifest the same phenotype. Another feature of the patients with KCNJ11 is that they manifest neurological dysfunction. Two patients manifested DEND syndrome in our series. One patient had the C166Y mutation, and the second patient had a novel R50G mutation. DEND syndrome has come to be recognized as resulting from mutations of certain specific residues, thus making the Kir6.2 conform into an open state by altering intrinsic gating kinetics (30, 32, 33). However, the residue of R50 was believed to be ATP-binding site in the N terminus in Kir6.2 (34), and the functional study of R50G showed that ATP sensitivity was profoundly reduced without changing the probability of the channel being open in the absence of ATP (35). Therefore, this is the first case of KCNJ11 mutation with DEND syndrome, which is caused by a decrease in the ATP binding affinity itself.

As for the ABCC8 mutation, we identified two novel mutations. SUR is a member of the ATP-binding cassette protein family and comprises 17 transmembrane helices and two nucleotide-binding folds (NBF1 and NBF2) (17). The 17 transmembrane helices are arranged in groups of five, six, and six, which are the hydrophobic transmembrane domains (TMD) 0, 1, and 2, respectively. The novel A90V and N1122D mutations are located in TMD0 and TMD2, respectively. Both TMD0 and TMD2, which are critical sites for potassium channel openers (36), are physically and functionally important regions. The reported mutations F132L (4) and H1023Y (5) are located in TMD0 and TMD2, respectively, and functional studies confirmed that these mutations reduced ATP sensitivity. Thus, the functional consequence of the novel mutations A90V and N1122D is likely to overactivate ß-cell ATP-sensitive K⁺ channels. The ABCC8 mutations are reported to contribute 12% of the total NDM and to be associated with TNDM rather than PNDM (5). However, the proportion of the ABCC8 mutation in our study group was small (two of 31, 6%). Two patients did not manifest TNDM in our study. Thus, it is hard to determine that the ABCC8 mutation is responsible for some form of NDM.

It is clinically very important to identify the mutation in KCNJ11 and ABCC8 in the patients with NDM because some mutations result in diabetes responsive to sulfonylurea therapy, which dramatically improved diabetes control and decrease risk for hypoglycemia (5, 18, 19). We found both genes were responsible for about 35% of Japanese patients with NDM. Thus, it is worth investigating the mutation to inform the families of the implications for the improvement in quality of life by switching from insulin therapy to sulfonylurea. Actually, some patients have begun to be treated with sulfonylurea (data not shown).

As for the FOXP3 mutation, we identified a novel mutation in a patient with a classic severe clinical course of IPEX (37). FOXP3 encodes a DNA-binding protein that is a member of the forkhead (FKH) family of transcription factors with a leucine zipper and Zn finger binding domain. The novel P367L mutation is located in the FKH domain, which is essential for DNA binding. Many of the other mutations that cause IPEX are also reported to involve the FKH domain (37).

Delineation of clinical characteristics in patients with the 6q24 abnormality and KCNJ11 and ABCC8 mutation is helpful for the clinical classification of NDM. More than half of the patients exhibited SGA resulting from insulin insufficiency in fetal life, consistent with previous reports (5, 6, 9). However, the extent and the frequency of SGA were not significantly different among these groups (Table 2). On the other hand, there were significant differences in the onset of diabetes between the 6q24 abnormality group and the other two groups of the KCNJ11 or ABCC8 mutation. That is, 1) the age was younger in the 6q24 abnormality group than in the other two groups, and all the patients with the 6q24 abnormalities manifested diabetes within the first month of life; 2) the frequency of DKA with a higher blood glucose level, which led to severe symptoms, was lower in the 6q24 abnormality group than in other two groups; and 3) the proportion of the patients with macroglossia at initial presentation was higher in the 6q24 abnormality group than in the other two groups. Molecular analysis led to a definite diagnosis in the patients with NDM. As for neurological manifestations, only one patient with pUPD(6) had developmental delay without seizure. However, this may not be due to pUPD(6) itself, because this patient was born as an extremely immature baby with perinatal asphyxia. Two patients with the KCNJ11 mutation presented with severe developmental delay and epilepsy (DEND syndrome). Thus, mutational analysis of KCNJ11 is warranted in patients with NDM and cryptogenic neurological dysfunction. On the other hand, two patients with unknown cause exhibited DEND. Further study will be needed to classify DEND syndrome clinically in detail according to some causes. These different clinical findings may prove of great help for the crucial decision of which gene to analyze in affected patients first. Moreover, investigating genetics of NDM could be useful not only for estimating the prognosis but also for conferring another therapeutic option.

	Acknowledgments

 
We express our sincere gratitude to all of the families that participated in our study. We thank the following collaborators: Hiroshi Arakawa, Department of Neonatology, Saitama Medical Center; Naoya Sasaki, Department of Pediatrics, Yamada Red Cross Hospital; Koji Tsubouchi, Department of Pediatrics, Mino Municipal Hospital; Toshi Tatematsu, Department of Pediatrics, Chubu-Rosai Hospital; Yayoi Tsuboi, Department of Pediatrics, Dokkyo University School of Medicine; Kazumichi Onigata, Department of Pediatrics and Developmental Medicine, Gunma University Graduate School of Medicine; Tateo Kuno, Faculty of Culture and Education, Saga University; Akio Takahashi, Department of Pediatrics, Morioka Children’s Hospital; Tomoko Fujikawa, Department of Perinatal Medicine, Sapporo Medical University; Tomoka Nishida and Fumie Shibata, Department of Pediatrics, National Kanazawa Hospital; Etsuro Tokuhiro, Department of Pediatrics, Odawara Municipal Hospital; Makito Tanaka, Department of Pediatrics/Developmental Pediatrics, Nagoya University Graduate School of Medicine; Shigeru Nishimaki, Department of Pediatrics, Yokohama City University School of Medicine; Junko Yoshimoto, Department of Pediatrics, Fukuyama Medical Center; Toshiro Nagai, Department of Pediatrics, Dokkyo Medical University, Koshigaya Hospital; Hiroshi Koyama, Department of Pediatrics, Kishiwada Tokusyukai Hospital; Naoki Kato, Department of Pediatrics, Tokyo Medical University; Takeshi Nitani, Department of Pediatrics, Faculty of Medicine, Toyama Medical and Pharmaceutical University; Yuki Abe, Department of Pediatrics, Niigata City General Hospital; Yoichi Onoue, Department of Pediatrics, Toyama Prefectural Central Hospital; Nobutaka Sasaki, Department of Pediatrics, Onomichi-Kosei General Hospital; Hideaki Haruna, Department of Pediatrics, Juntendo University School of Medicine; Makoto Yoshino, Department of Pediatrics, Kurume University School of Medicine; and Mayuki Oku, Department of Neonatology, Gifu Prefectural Gifu Hospital.

	Footnotes

 
Disclosure Statement: The authors have nothing to disclose.

First Published Online July 17, 2007

Abbreviations: DEND, Developmental delay, epilepsy, and neonatal diabetes; DKA, diabetic ketoacidosis; FKH, forkhead; IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked; NDM, neonatal diabetes mellitus; PNDM, permanent NDM; pUPD(6 ), paternal uniparental disomy of chromosome 6; SGA, small for gestational age; TNDM, transient NDM.

Received March 2, 2007.

Accepted July 11, 2007.

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