Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-0286
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2844-2847
Copyright © 2007 by The Endocrine Society
Exonic Duplication of the Hepatocyte Nuclear Factor-1ß Gene (Transcription Factor 2, Hepatic) as a Cause of Maturity Onset Diabetes of the Young Type 5
Claire Carette,
Christelle Vaury,
Anne Barthélémy,
Séverine Clauin,
Jean-Pierre Grünfeld,
José Timsit and
Christine Bellanné-Chantelot
Department of Immunology and Diabetology (C.C., J.T.), Université René Descartes Paris 5, AP-HP Hôpital Cochin, F-75014 Paris, France; Department of Molecular Biology (C.V., S.C.), AP-HP Hôpital Saint Antoine, F-75012 Paris, France; Department of Pediatry (A.B.), Centre Hospitalier Général de Montelimar, F-26216 Montelimar, France; Department of Nephrology (J.-P.G.), AP-HP Hôpital Necker Enfants Malades, F-75015 Paris, France; and Department of Cytogenetics (C.B.-C.), AP-HP Hôpital Saint Antoine, Université Pierre et Marie Curie Paris 6, F-75012 Paris, France
Address all correspondence and requests for reprints to: Claire Carette, Service d’Immunologie-Diabétologie, 27 rue du Faubourg Saint Jacques, Hôpital Cochin, 75014 Paris, France. E-mail: claire.carette{at}cch.aphp.fr.
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Abstract
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Context: Maturity onset diabetes of the young (MODY) type 5 has been described as the association of early-onset diabetes and renal disease. Actually, MODY5 encompasses multiple phenotypes, including nondiabetic progressive renal failure, kidney and genital tract malformations, atypical familial hyperuricemic nephropathy, pancreas atrophy, and liver test abnormalities. The occurrence of MODY5 has been associated with various molecular abnormalities of TCF2, including missense, nonsense, small insertion/deletions, and splice site mutations, as well as large genomic deletions or single exonic deletion of TCF2.
Design: Using quantitative multiplex PCR amplification of short fluorescent fragments, we have analyzed the TCF2 gene in a French family of which three relatives presented a MODY5 phenotype. The proband had an extended clinical phenotype, including hyperuricemic nephropathy and early gout, chronic renal failure, renal morphological abnormalities, abnormal liver tests, and diabetes. His son had almost no clinical expression of the disease, whereas his grandson had a restricted but severe renal phenotype present from birth.
Results: We show that a duplication of the exon 5 of TCF2 is responsible for the MODY5 phenotypes in this family.
Conclusions: Thus, we describe a novel molecular mechanism that may be responsible for MODY5, and we emphasize the wide intrafamilial variability of MODY5 expressivity. These observations suggest that the diagnosis of MODY5 may be raised even in subjects with partial phenotypes. They also confirm that quantitative multiplex PCR amplification of short fluorescent fragments analysis should be the first step of genetic screening in patients with a MODY5 phenotype.
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Introduction
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MATURITY ONSET DIABETES of the young (MODY) type 5 is due to molecular abnormalities of the hepatocyte nuclear factor (HNF)-1ß encoded by the TCF2 gene (1). MODY5 was first reported as the association of early-onset diabetes and renal disease. Several renal phenotypes have been described in patients with MODY5, including renal cysts (2, 3, 4, 5), familial glomerulocystic kidney disease (4, 5, 6, 7, 8, 9, 10), oligomeganephronia (11), solitary functioning kidney (5, 9), horseshoe kidney (5, 11), and impaired renal function. Actually, in adult patients, MODY5 encompasses a wide clinical spectrum comprising diabetes, pancreas atrophy with subclinical exocrine deficiency, nondiabetic progressive renal failure, kidney and genital tract malformations, and liver test abnormalities (5, 12, 13, 14). Atypical familial hyperuricemic nephropathy has also been reported in few kindreds (4, 5, 15). The clinical defects associated with TCF2 abnormalities are related to the expression pattern of HNF-1ß during the early stages of organogenesis of the urinary and genital tracts, liver and biliary ducts, and pancreas, as described in mice and humans (3, 16).
MODY5 was first related to heterozygous mutations of TCF2, including missense, nonsense, small insertion/deletions, and splice site mutations (5, 12, 13). Mutations predominantly cluster in the DNA binding domain (4). Additionally, using quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF), we have shown that in one third of adult patients with a MODY5 phenotype, the disease is related to large deletions that encompass the whole TCF2 gene; in one patient, MODY5 was due to the deletion of a single exon (13). However, some cases with a typical MODY5 phenotype remain unexplained, and no deletion or mutation of TCF2 can be found. This suggests that other genes may be responsible for this phenotype or that other molecular abnormalities of TCF2 may exist.
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Subjects and Methods
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In this report we used QMPSF to show that a duplication of the exon 5 of TCF2 (Gly349_M402dup) is responsible for a MODY5 phenotype in a French family.
In the proband (III-2; Fig. 1
), the first manifestation of the disease was an articular gout that occurred at age 10. A mild renal insufficiency was also present, and a left pelvicaliceal dilatation related to a ureteric stricture was diagnosed. The patient was examined in our department at age 31. Creatinine clearance was 46 ml/min·1.73m2. Ultrasonography showed that the left kidney was atrophic; the right kidney was normal except for the presence of a single cortical cyst of 12-mm diameter. Intravenous urography confirmed that only the right kidney was functional. A mild fasting hyperglycemia (6.8 mM) was diagnosed by systematic screening at age 36. Body mass index (BMI) was 27.9 kg/m2, and the patient was treated by diet. Despite weight loss (BMI 24.6 kg/m2), hyperglycemia worsened. The patient was treated with glipizide. Because of the progression of renal failure, insulin therapy was started at age 51, and good glycemic control was achieved [glycosylated hemoglobin (HbA1c) 6.5%]. At the last follow-up (age 57), the patient had no diabetic retinopathy, and creatinine clearance was 25 ml/min·1.73m2. An increase in the plasma level of 
-glutamyl transpeptidase was also noticed (up to 4.4 times the upper value of normal range) on several occasions.
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FIG. 1. Pedigree of a French family with a duplication of the exon 5 of the TCF2 gene. Chronic renal failure (CRF) is indicated by a left-filled symbol and diabetes mellitus (DM) by a right-filled symbol. The proband (III-2) is indicated by the arrow. The genotype of each subject is indicated as: normal allele (N), duplication of exon 5 (Dup), and not determined (nd). The presence or absence of chronic renal failure, diabetes mellitus, hyperuricemia, and liver test abnormalities are indicated (yes/no). Subjects’ present age, age at diagnosis of renal failure, and age at diagnosis of diabetes are indicated (years).
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The proband’s son (IV-3) had no particular medical history. Systematic screening at age 25 showed a mild increase in his creatinine plasma level (138 µM, creatinine clearance 80 ml/min·1.73m2). At the last follow-up (age 34), the creatinine level was 150 µM. Renal ultrasonography did not show any abnormality. Fasting blood glucose concentrations ranged 5.4–6.0 mM, and HbA1c was consistently normal (range 5–5.2%). Liver tests and uricemia were normal.
In the proband’s grandson (V-1), fetal ultrasonography revealed bilateral renal hyperechogenicity. At birth, the creatinine plasma level was 123 µM (creatinine clearance 23 ml/min·1.73m2) and was associated with metabolic acidosis. Postnatal renal ultrasonography showed bilateral renal atrophy with multiple microcysts. Renal function improved within the following weeks. Creatininemia was 50 µM at 2 and 6 months of age, and 88 µM at 4.5 yr of age (creatinine clearance 68 ml/min·1.73m2). At the last follow-up, fasting blood glucose, HbA1c, and liver tests were normal, whereas uricemia was increased (358 µM).
In the proband’s father (II-2), diabetes mellitus was diagnosed at age 45 (BMI 29.7 kg/m2) and was treated with metformin, then glipizide. Chronic renal failure was diagnosed at age 59 (creatinine plasma level 230 µM, creatinine clearance 33 ml/min·1.73m2). Renal ultrasonography showed a single right kidney. At this time, the patient had no diabetic retinopathy. Creatinine levels increased up to 400 µM (creatinine clearance 19 ml/min·1.73m2) just before death from alcoholic cirrhosis at age 63. A history of chronic renal failure was also recorded in the proband’s aunt (II-1) and grandmother (I-1).
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Results
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The association of diabetes mellitus, hyperuricemia, and functional and renal abnormalities led us to screen the TCF2 gene. All patients gave written informed consent for genetic testing. Using the QMPSF approach as previously described (13), a heterozygous duplication of the fifth exon was identified in the proband (III-2) and subsequently detected in the two other affected relatives (IV-3 and V-1) (Table 1 and Fig. 1
). In these three patients, the duplication was further confirmed by real-time quantitative PCR based on SYBR Green I fluorescence (Applied Biosystems, Inc., Foster City, CA) (data not shown). We were not able to amplify by long-range PCR the genomic region located between the exons 4 and 6 due to the large size of intron 4 and intron 5, which are 20,914 and 5,454 base pairs, respectively. To examine the effect of the duplication of exon 5, we amplified TCF2 mRNA transcript from Epstein-Barr virus-transformed lymphoblastoid cells of the proband and from freshly isolated peripheral blood leukocytes of two affected relatives, using previously described methods (17). We only observed the wild-type transcript. This suggests either that the mutant transcript was present, but at a very low level, undetectable in the tested cells, or that it was degraded by the nonsense-mediated decay mRNA surveillance pathway (17). Consequently, we were not able to locate accurately the duplication of exon 5 within the TCF2 genomic sequence. We hypothesize that the duplicated exon is located in the surrounding intronic regions of intron 4 or intron 5 of TCF2 because it has been shown in the literature that most duplications are tandem duplications head-to-tail in orientation (18).
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Discussion
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In this kindred, several peculiarities of MODY5 are emphasized.
First, the wide intrafamilial clinical variability of the MODY5 phenotype is clearly exemplified. In the proband (III-2) the clinical phenotype included diabetes, abnormal liver tests, kidney morphological abnormalities, nondiabetic progressive renal failure, and a juvenile hyperuricemia with gout. By contrast, in his grandson (V-1) the disease was restricted to a renal phenotype, but this child was only 4 yr old at the last follow-up. Similarly, multicystic renal dysplasia and renal hypoplasia associated to TCF2 abnormalities have been recently reported in two cohorts of children who did not exhibit any extrarenal manifestations, particularly diabetes (11, 19). Only long-term follow-up of such cohorts will allow determining whether other clinical manifestations related to MODY5 will occur or if phenotypes restricted to renal disease do exist. In this respect, at age 34, subject IV-3 had almost no clinical expression of the disease. Such a variable expressivity may make the diagnosis of MODY5 and genetic counseling very difficult.
Second, this pedigree highlights that renal manifestations are the predominant defect of MODY5 and often precede the onset of diabetes. This has been observed both in adult and pediatric patients (11, 12, 13). These observations suggest a crucial role for HNF-1ß in kidney differentiation and function, and the absence of rescue by other transcription factors expressed at the same stage of organogenesis. By contrast, the clinical expression of diabetes is usually characterized by a slow progressive defect in adulthood, although rare cases of an acute onset at a young age have been reported (12, 20). In a small number of patients, it has been shown that TCF2 mutations are associated with insulin resistance (20). Thus, diabetes may occur only when insulin secretion becomes too low to compensate for insulin resistance. Altogether, these observations suggest that some mechanisms may exist, allowing partial compensation for pancreatic defects.
Third, yet the spectrum of TCF2 molecular abnormalities was restricted to point mutations and to heterozygous deletions of the whole gene. More than 40 different TCF2 mutations have been reported, and most of them are private (5, 13). Heterozygous deletion of TCF2 accounts for one third of cases in adult patients and two third of cases diagnosed during the neonatal period or during childhood (11, 13). Here, we have described a novel molecular mechanism responsible for MODY5, i.e. the duplication of a single exon of TCF2. Interestingly, this exonic duplication was responsible for heterogeneous MODY5 phenotypes within a single family. This observation fits well with the absence of correlation between the phenotype and genotype observed both in pediatric and adult cohorts. Indeed, no difference in the clinical characteristics could be found between patients with a TCF2 point mutation and those with a whole gene deletion (11, 13).
Duplications are probably a rare mechanism of MODY5. Indeed, using the same QMPSF technique, we have detected no other duplication among 79 unrelated patients with MODY5 and a TCF2 anomaly (data not shown). The rare occurrence of duplications compared with deletions may be explained by differences in the involved molecular mechanisms. In contrast with deletions due to recurrent rearrangements formed by homologous recombination between low-copy repeats, the underlying molecular mechanism involved in duplication is probably more complex. It has been proposed that duplications might be related to a particular genomic architecture that would lead to genomic instability (18). This architecture might be unique on the genome, explaining the low frequency of such molecular events. This case reinforces the value of genomic rearrangement detection as the first step of genetic screening in patients with a MODY5 phenotype.
In conclusion, this report contributes to understanding further the molecular mechanisms that may be responsible for MODY5. It is now ascertained that the phenotype of subjects with a TCF2 molecular abnormality is highly variable from one family to another, as well as within a given family. This suggests that other genetic and/or environmental factors could play a role in the pattern and severity of MODY5. At last, this reported kindred argues for the existence of restricted phenotypes in patients with TCF2 molecular abnormalities.
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Footnotes
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Disclosure Statement: The authors have nothing to disclose.
First Published Online April 17, 2007
Abbreviations: BMI, Body mass index; HbA1c, glycosylated hemoglobin; HNF, hepatocyte nuclear factor; MODY, maturity onset diabetes of the young; QMPSF, quantitative multiplex PCR amplification of short fluorescent fragments; TCF2, transcription factor 2, hepatic.
Received February 8, 2007.
Accepted April 11, 2007.
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Abstract
Introduction
