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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2905-2908
Copyright © 2004 by The Endocrine Society

Neonatal Diabetes Mellitus and Neonatal Polycystic, Dysplastic Kidneys: Phenotypically Discordant Recurrence of a Mutation in the Hepatocyte Nuclear Factor-1ß Gene Due to Germline Mosaicism

Tohru Yorifuji, Keiji Kurokawa, Mitsukazu Mamada, Tsuyoshi Imai, Masahiko Kawai, Yoshikazu Nishi, Seiichiro Shishido, Yukihiro Hasegawa and Tatsutoshi Nakahata

Department of Pediatrics (T.Y., K.K., M.M., T.I., M.K., T.N.), Kyoto University Hospital, Kyoto 606-8507; Department of Pediatrics (Y.N.), Hiroshima Red Cross Hospital, Hiroshima 730-8619; and Departments of Urology (S.S.) and Endocrinology and Metabolism (Y.H.), Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo 204-8567, Japan

Address all correspondence and requests for reprints to: Tohru Yorifuji, M.D., Ph.D., Department of Pediatrics, Kyoto University Hospital, 54 Shogoin Sakyo, Kyoto 606-8507, Japan. E-mail: yorif{at}kuhp.kyoto-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Mutations in the gene coding for hepatocyte nuclear factor-1ß (HNF-1ß) have been known to cause a form of maturity-onset diabetes of the young (MODY5), which is usually characterized by dominantly inherited adolescence-onset diabetes mellitus associated with renal cysts. This report, however, describes recurrence of a novel missense mutation in the HNF-1ß gene, S148W (C443G), in two sibs, one with neonatal diabetes mellitus and the other with neonatal polycystic, dysplastic kidneys leading to early renal failure. The former patient had only a few small renal cysts with normal renal functions, and the latter had only a transient episode of hyperglycemia, which resolved spontaneously. Interestingly, both parents were clinically unaffected, and PCR restriction fragment length polymorphism analysis showed that the mother was a low-level mosaic of normal and mutant HNF-1ß, which suggested that the recurrence was caused by germline mosaicism. This is the first report of permanent neonatal diabetes mellitus caused by a mutation of the HNF-1ß gene as well as the first report of germline mosaicism of this gene. In addition, the two cases described here show that additional factors, genetic or environmental, can have a significant influence on the phenotypic expression of HNF-1ß mutations.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
HEPATOCYTE NUCLEAR FACTOR-1ß (HNF-1ß) is a homeodomain-containing, tissue-specific transcription factor, which was initially isolated from hepatocytes (1). It functions as a homodimer or as a heterodimer with the structurally related HNF-1{alpha} and transactivates a variety of proteins, including {alpha}- and ß-fibrinogen, albumin, {alpha}-fetoprotein, transthyretin, {alpha}1-antitrypsin, and GLUT2 (1). In adult animals, the HNF-1ß gene is expressed mainly in the kidney, liver, intestine, lungs, and pancreas, whereas in early embryos the gene is widely expressed in the visceral endoderm (1). Homozygous ablation in mice results in intrauterine death associated with disorganized visceral endoderm (2, 3), whereas heterozygous mice remain asymptomatic. In humans, however, it has been shown that heterozygous mutations of the HNF-1ß gene are associated with a form of maturity-onset diabetes of the young (MODY5), which is characterized by dominantly inherited diabetes mellitus associated with renal cysts (4). To date, 15 different mutations have been identified in a total of 17 families (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17).

This report concerns two sibs with an identical mutation, S148W (C443G), in the HNF-1ß gene. Interestingly, these sibs presented with very discordant phenotypes, that is, one with permanent neonatal diabetes mellitus and the other with neonatal polycystic, dysplastic kidneys leading to early renal failure. Despite recurrence of this phenotypical abnormality in the sibs, both parents were phenotypically normal. Further molecular analysis indicated that the recurrence was caused by germline mosaicism, which has not been previously reported for this gene. In addition, our cases suggest that additional factors, genetic or environmental, can have a significant influence on the phenotypic expression of HNF-1ß mutations.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Patient 1 is a Japanese girl who was born after 39 wk of uneventful pregnancy with a birth weight of 1896 g (small for gestational age). Her parents are healthy and nonconsanguineous, and there was no family history of diabetes mellitus. On the 15th day of life, she had a seizure and was brought to a local hospital. Laboratory test results showed hyperglycemia and severe metabolic acidosis with a blood sugar level of 1000 mg/dl (55.5 mmol/liter) and arterial pH of 6.98. Although her condition gradually stabilized in response to iv insulin therapy, she remained profoundly retarded and epileptic. Magnetic resonance imaging (MRI) of the brain on the 20th day of life showed bilateral subacute brain infarction. Since then, her diabetes mellitus has persisted and fluctuated in severity necessitating intermittent (1–13 months for each course) use of insulin. From the age of 6 onward, she required daily insulin injections. Currently she is 11 yr old. Her blood creatinine and urea nitrogen remain within normal range, but MRI of the kidneys has identified a slightly small right kidney, which contains two small cysts, and a normal left kidney. The pancreas was thin, but the length was normal. Otherwise, she does not have other features, such as genital anomalies, liver dysfunction, or hyperuricemia previously reported for a fraction of patients with HNF1ß abnormalities (7, 12, 17).

Patient 2 is the younger brother of patient 1. He was born after 39 wk of pregnancy weighing 2895 g. He presented with tachypnea immediately after birth. Blood examination on d 1 showed renal dysfunction with 19 mg/dl (6.78 mmol/liter) blood urea nitrogen and 2.5 mg/dl (221 µmol/liter) creatinine. Abdominal ultrasound disclosed a multicystic left kidney and high echoic right kidney with multiple small cysts.

The boy’s renal function gradually deteriorated leading to an end-stage renal failure at 2 yr of age, followed by renal transplantation performed when he was 3. Chronic rejection of the graft necessitated continued use of glucocorticoid and tacrolimus. During the monthly follow-up, he remained euglycemic until 5 yr of age when he suffered right epididymitis. Blood glucose at 474 mg/dl (26.3 mmol/liter) was noted during the episode but returned to normal within several days. Since then, he has remained euglycemic. As in patient 1, liver dysfunction has not been observed throughout his clinical course. The sibs’ mother showed a normal response (blood glucose and insulin) to an oral glucose tolerance test. The study was performed under informed consent, and the protocol was approved by the Institutional Review Board of Kyoto University Hospital.

Mutational analysis

Genomic DNA was isolated from peripheral blood leukocytes using a QIAmp DNA mini kit (QIAGEN, Hilden, Germany) in accordance with the manufacturer’s instructions. All nine exons of the HNF1-ß gene were then amplified together with the exon-intron boundaries in 25-µl reactions containing 50 ng of genomic DNA, 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 15 mM MgCl2, 0.01% (wt/vol) gelatin, 12.5 pmol of each primer, and 0.5 U AmpliTaq Gold DNA polymerase (Perkin-Elmer, Boston, MA). The initial denaturation at 94 C for 10 min was followed by 30 cycles of denaturation at 94 C for 30 sec, annealing at 55 C for 30 sec, and extension at 72 C for 30 sec. The sequences of the primers are available from the authors. The amplified products were purified with the Wizard PCR Preps DNA Purification System (Promega, Madison, WI) and one fifth of the purified products was directly sequenced with the BigDye Terminator Cycle Sequencing Kit (Roche, San Francisco, CA).

Paternity testing

Paternity testing was performed by using highly polymorphic markers, D7S440, D10S1653, D11S4046, D16S403, D16S497, D19S418, D20S195, D21S1256, and DXYS233. Briefly, for each marker, one of the primers was end-labeled with 32P by T4-polynucleotide kinase, PCR was then performed in 10-µl reactions containing 20 ng of genomic DNA, 12.5 pmol each of labeled and unlabeled primer, and the same buffer as for the genomic DNA amplification. The initial denaturation at 94 C for 10 min was followed by 32 cycles of 94 C for 1 min, 55 C for 1 min, and 72 C for 1 min. Two volumes of formamide-containing stop buffer were added, after which the mixture was heat denatured at 85 C for 5 min, and 2 µl was run through a 6% denaturing polyacrylamide gel. The gel was then visualized with an image analyzer (Fuji, Tokyo, Japan).

PCR restriction fragment length polymorphism (RFLP)

For detection of low-level mosaicism associated with the S148W mutation, exon 2 of the HNF-1ß gene was amplified as for the mutation analysis described above, but this time with 40 cycles of amplification. Four microliters of the PCR product were digested with 5 U of BanI in a 5-µl reaction at 50 C for 20 h and then electrophoresed through a 10% polyacrylamide gel, which was then stained with ethidium bromide.

Functional analysis

A mammalian expression plasmid containing the full-length HNF-1ß cDNA under control of a cytomegalovirus (CMV)-IE promoter (pCMV-WT) and a reporter plasmid containing the firefly luciferase gene and a fragment (–1296/+312) of the GLUT2 promoter (pGL3-GT2) were kindly donated by Dr. Takeda of Gunma University, Japan (18). The S148W mutation was introduced into pCMV-WT using the Quick Change site-directed mutagenesis kit (Stratagene, La Jolla, CA). The sequence of the mutant plasmid, pCMV-S148W, was verified by direct sequencing of the entire plasmid.

A human cervical carcinoma cell line, HeLa, was plated at a density of 2 x 105 cells per 3-cm plastic dish. Twenty-four hours later, 1000 ng of reporter plasmid was introduced into the cells together with various combinations of expression plasmids (pCMV-WT, pCMV-S148W, or an empty pCMV), by using the Superfect transfection reagents (QIAGEN) in accordance with the manufacturer’s instructions. After 2 h of transfection, the DNA mixture was removed and the culture continued with fresh medium. After 48 h of incubation, the cells were washed twice with PBS, after which 1 ml of lysis buffer [25 mM Tris-HCl (pH 7.5), 2 mM dithiothreitol, 10% (vol/vol) glycerol, 1% (vol/vol) Triton X-100] was added to each dish. The lysates were transferred to 1.5-ml microfuge tubes and then centrifuged for 3 min at 15,000 rpm. The supernatant was recovered, and 5 µl of the supernatant was added to 50 µl of luciferin mix [137 mM NaCl, 2.7 mM KCl, 4.3 mM Na2HPO4, 1.4 mM KH2PO4, 20 mM Tricine, 1.07 mM (MgCO3)4Mg(OH)2·5H2O, 2.67 mM MgSO4, 0.1 mM EDTA, 33.3 mM dithiothreitol, 270 µM coenzyme A, 470 µM luciferin, 530 µM ATP]. The luminescence was immediately measured with a TD-20/20 Luminometer (Turner Designs, Sunnyvale, CA).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Direct sequencing of the amplified genomic fragments revealed an identical missense mutation S148W (C443G) in exon 2 within the pseudo-POU domain of the HNF-1ß gene in both patients (Fig. 1Go). Both were heterozygotes of S148W/WT, and no other mutations were found in any other exons, exon-intron boundaries, or the immediate 5' flanking sequences. As shown in Fig. 1Go, the parents appeared normal by direct sequencing of exon 2. Analysis of the highly polymorphic markers, D7S440, D10S1653, D11S4046, D16S403, D16S497, D19S418, D20S195, D21S1256, and DXYS233, confirmed paternity (data not shown). Because the S148W mutation generates a novel BanI restriction site, we next used PCR-RFLP analysis to determine the possible presence of mosaicism. As shown in Fig. 2Go, the mother proved to be a low-level mosaic of normal and S148W (C443G). Cross-contamination of DNA from patients 1 or 2 is unlikely because the 133-bp band was not observed in the negative control without genomic DNA. In addition, paternity testing gels described above did not show any signs of maternal DNA being contaminated by DNA from patients 1 or 2. The recurrence of the same mutation in the two sibs, therefore, was caused by germline mosaicism in the maternal gonads. By the same PCR-RFLP analysis, S148W was not present in 50 normal volunteers (healthy laboratory workers and medical students at Kyoto University, data not shown).



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  		FIG. 1. Direct sequencing of amplified exon 2 of the HNF-1ß gene. A, Father; B, mother; C, patient 1; D, patient 2. Arrows indicate the position of nucleotide 443. Patients 1 and 2 were heterozygotes of G/C at this position. Both parents appeared to be homozygotes of G/G; however, a small peak of C was visible in the mother’s position 443.

 


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  		FIG. 2. Detection of the S148W(C443G) mutation by PCR-RFLP analysis. Exon 2 of the HNF-1ß gene was amplified and digested with BanI. The wild-type allele was cleaved into 177- and 159-bp fragments and the S148W (C443G) allele into 177-, 133-, and 26-bp fragments. a, Father; b, patient 1; c, patient 2; d, mother; e, negative control without genomic DNA. The arrow shows the position of the 133-bp fragment.

 
To examine the functional consequences of the S148W mutation, we generated a mutant expression plasmid containing the S148W mutation, pCMV-S148W, by site-directed mutagenesis. The HeLa cells were then transfected with the reporter plasmid (pGL3-GT2) and various combinations of the wild-type (pCMV-WT), mutant (pCMV-S148W), and empty (pCMV) plasmids. Preliminary experiments with increasing amounts of expression plasmids showed that, in the presence of 1000 ng of pGL3-GT2 per dish, the luminescence reached a plateau at 10–15 ng of pCMV-WT or pCMV-S148W (data not shown). Therefore, additional experiments were performed with 1000 ng of pGL3-GT2 and 10 ng each of expression plasmids. As shown in Fig. 3Go, the transactivation potential of pCMV-S148W was reduced to 13.0% of that of the wild-type plasmid (pCMV-WT), confirming the loss-of-function nature of this mutation. In addition, when pCMV-WT and pCMV-S148W were cotransfected, the luminescence was reduced to 51.5% of that of pCMV-WT alone. This effect was not observed for the empty plasmid (pCMV). These results suggest that the S148W mutation exerts its effect partly by a dominant-negative mechanism as well.



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  		FIG. 3. Functional analysis of the S148W (C443G) mutation of HNF-1ß. Wild-type (pCMV-WT), mutant (pCMV-S148W), or empty plasmids (pCMV) were transfected into HeLa cells with the reporter plasmid (pGL3-GT2). The cells were lysed 48 h later, and the transactivation of the GLUT2 promoter was measured as the luminescence per microgram of protein. The results were expressed as percent luminescence in comparison with the luminescence by pCMV-WT alone. The mean and the SD of three independent experiments are shown.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
MODY is, by definition, a dominantly inherited, insulin-deficient diabetes mellitus with onset usually before 25 yr and often in childhood or in adolescence. Different types of MODY have been shown to be caused by mutations in different genes; MODY1 by the HNF-4{alpha} gene, MODY2 by the glucokinase gene, MODY3 by the HNF-1{alpha} gene, MODY4 by the insulin promoter factor-1 gene, MODY5 by the HNF-1ß gene, and MODY6 by the NeuroD1 gene (19). Among these, MODY5 is characterized by the presence of renal cysts in patients with MODY (13). In addition, some patients also suffer from genital anomalies or liver dysfunction (7, 12). The renal abnormalities in MODY5 cover a wide spectrum even within the same family. Reported renal abnormalities include a few asymptomatic renal cysts, severe multicystic dysplastic kidneys, noncystic renal parenchymal disease, oligomeganephronia, small hyperechoic kidneys, or even horseshoe kidneys. The mutations in HNF-1ß have also been implicated in familial glomerulocystic kidney disease or atypical familial juvenile hyperuricemic nephropathy (16, 17). The severity and the age at the onset of diabetes mellitus also varies, with the earliest reported onset occurring at 10 yr of age.

In this study, we have identified a novel missense mutation, S148W (C443G), in the pseudo-POU domain of the HNF-1ß gene. As shown in the functional studies, this mutation appears to impair the function of HNF-1ß by loss-of-function and dominant negative mechanisms. This is not surprising because the mutant protein retains the dimerization domain in the N-terminal 31 amino acids and has a mutated pseudo-POU domain that determines the target sequence specificity of the HNF-1ß molecule. Similar mechanisms have been shown for the R177X mutation and partly for the A263fsinsGG mutation as well (18).

The family presented in this report shows several unusual features that can be expected to broaden our options for inclusion of MODY5 as a diagnostic possibility. First, this family is the first reported case of recurrence due to germline mosaicism in a parent. MODY5 should therefore be included as a diagnostic option even in cases apparently inherited in an autosomal recessive manner. Second, our patient 1 presented with permanent neonatal diabetes mellitus. So far, only a few genetic mutations have been identified that may account for severe permanent neonatal diabetes mellitus. These include homozygous mutations in the insulin promoter factor I gene (20) causing agenesis of the pancreas, in the GLUT2 gene causing Fanconi-Bickel syndrome (21), in the glucokinase gene (22), or hemizygous mutation in the FOXP3 gene causing X-linked neonatal diabetes mellitus, enteropathy, and endocrinopathy syndrome (23). Ours is the first report of permanent neonatal diabetes mellitus caused by a mutation in the HNF-1ß gene. Unlike the genes identified previously, a mutation in the HNF-1ß gene does not cause neonatal diabetes mellitus by itself. Other factors, environmental and/or genetic, are also required for the development of diabetes in the neonatal period. Third, the phenotypic features of the two sibs were so different that they appeared to suffer completely different disorders. Patient 1 had normal renal functions, and renal cysts were detectable only by careful examination with MRI. Likewise, patient 2 showed only transient signs of hyperglycemia, which spontaneously returned to normal. In isolated cases, it would be difficult to arrive at a diagnosis of HNF-1ß abnormality. For patient 2, however, this diagnosis was clinically important because this patient underwent kidney transplantation and was taking glucocorticoid and tacrolimus on a continuous basis. Both of these agents may accelerate the development of overt diabetes mellitus. Patient 2 now is under strict observation by an endocrinologist, working in cooperation with nephrologists.

It remains unclear why these two sibs with an identical mutation presented with discordant phenotypes. It appears that additional factors, genetic or environmental, can have a significant influence on the phenotypic expression of HNF-1ß mutations. One such candidate is the difference in the genotype of HNF-1{alpha}, which is known to form a heterodimer with HNF-1ß. In our cases, patient 1 had Asn487Ser/WT and patient 2 had Asn487Ser/Asn487Ser as the HNF-1{alpha} genotype (unpublished data). Although Asn487Ser is a previously reported single-nucleotide polymorphism and not considered a mutation, it is still possible that this difference in the HNF-1{alpha} background somehow affected the phenotypic presentation of the HNF-1ß mutation. Accumulation of more data of genotype-phenotype correlation for a number of patients is necessary to address this possibility.


   Acknowledgments
 
We thank Professor Jun Takeda of Gunma University for his generous gift of pCMV-WT and pGL3-GT2.


   Footnotes
 
Abbreviations: CMV, Cytomegalovirus; HNF-1ß, hepatocyte nuclear factor-1ß; MODY, maturity-onset diabetes of the young; MRI, magnetic resonance imaging; RFLP, restriction fragment length polymorphism.

Received October 21, 2003.

Accepted February 16, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals