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Human Molecular Genetics Pages 583-586

Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3)
Introduction
Results
Discussion
Materials And Methods
Acknowledgements
References

Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3)

Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3) Martine Vaxillaire1,2, Mathias Rouard3, Kazuya Yamagata3,4, Naohisa Oda5, Pamela J. Kaisaki3,4, V. Vicky Boriraj4, Jean-Claude Chevre1, Valérie Boccio1, Roger D. Cox2, G. Mark Lathrop2, Philippe Dussoix6, Jacques Philippe6, José Timsit7, Guillaume Charpentier8, Gilberto Velho9, Graeme I. Bell3,4,5 and Philippe Froguel1,*

1CNRS EP10, Institut Pasteur de Lille & CHU de Lille, 1 rue du Professeur Calmette, BP 245, 59019Lille,France,2Wellcome Trust Centre for Human Genetics, Windmill Road,Oxford OX3 7BN,UK,3Department of Biochemistry & Molecular Biology,4Howard Hughes Medical Institute,5Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC1028,Chicago, Illinois 60637,USA,6Unité de Diabétologie Clinique, Hôpital Cantonal Universitaire de Genève, 24 rue Micheli-du-Crest, 1211Genève 14,Switzerland,7Service d'Immunologie Clinique, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015Paris,France,8Service d'Endocrinologie, Centre Hospitalier Gilles de Corbeil, 59 boulevard Henri Dunant, 91108Corbeil-Essonnes,France and9INSERM U358, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75010Paris,France

Received November 26, 1996;Revised and Accepted January 23, 1997

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. Recent studies have shown that mutations in the two functionally related transcription factors, hepatocyte nuclear factor 4 alpha (HNF-4[alpha]) and hepatocyte nuclear factor 1 alpha (HNF-1[alpha]) are associated with the MODY1 and MODY3 forms of diabetes respectively, whereas mutations in the enzyme glucokinase are the cause of the MODY2 form. We have examined 10 unrelated Caucasian families in which MODY/NIDDM co-segregated with markers forMODY3 for mutations in the HNF-1[alpha] gene (TCF1). Ten different mutations were observed in these families, all of which co-segregated with diabetes. There were no obvious relationships between the nature of the mutations observed (i.e. frameshift, nonsense, or missense) or their location in the gene with clinical features of diabetes (age at onset, severity) in these families. The mechanisms by which mutations in the HNF-1[alpha] gene cause diabetes mellitus are unclear but might include abnormal pancreatic islet development during foetal life thereby limiting their later function, as well as impaired transcriptional regulation of genes that play a key role in normal pancreatic beta cell function.

INTRODUCTION

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, usually before 25 years of age, autosomal dominant inheritance (1 ) and a primary defect in insulin secretion (2 -6 ). MODY occurs world-wide and we have estimated that 13% of Caucasian families collected in France have this form of diabetes (7 ). Genetic studies have previously localised three MODY genes on chromosomes 20q (MODY1) (8 ), 7p (glucokinase/MODY2) (9 ) and 12q (MODY3) (10 ). MODY2 appears to be the most common form of MODY in France and so far 36 different glucokinase mutations have been described in 42 unrelated families (11 ). Clinical studies have shown that mutations in glucokinase/MODY2 result in mild chronic hyperglycaemia due to reduced pancreatic beta cell responsiveness to glucose (2 ,3 ), and decreased net accumulation of hepatic glycogen and increased hepatic gluconeogenesis following meals (12 ). In contrast, the clinical phenotypes of MODY1 and MODY3 are characterised by severe insulin secretory defects (4 -6 ), and by major hyperglycaemia associated with microvascular complications (1 ,13 ).

Recently, Yamagataet al. (14 ) showed thatMODY3 was the gene encoding the hepatocyte nuclear factor 1 alpha (HNF-1[alpha], symbol TCF1). This transcription factor is involved in tissue specific regulation of liver genes (15 ), and is also expressed in pancreatic islets and other tissues. Seven different mutations in HNF-1[alpha] were found to co-segregate with NIDDM in seven MODY families (14 ).MODY1 was identified as the gene encoding the hepatocyte nuclear factor 4 alpha (HNF-4[alpha]) (16 ), a member of the steroid/thyroid hormone receptor superfamily and upstream regulator of HNF-1[alpha] expression.

In this study, we have examined ten unrelated Caucasian families in which MODY/NIDDM co-segregated with markers forMODY3 (10 ) for mutations in the HNF-1[alpha] gene. We report the identification of ten different mutations which co-segregated with diabetes in these families.

RESULTS

The ten exons and flanking intronic regions of one affected member from each of ten MODY3-linked families (nine French and one Swiss) (Fig.1 ) were amplified using PCR and sequenced directly. Ten different mutations were identified in these families (Table1 ), each of which co-segregated with diabetes. Of these the P379fsdelCT mutation was previously reported in one British family (14 ) and the remainder are newly described. The five frameshift and two nonsense mutations are predicted to lead to the synthesis of a truncated protein. The three missense mutations, all of which are located in exon 2, are mutations of residues that are conserved in the sequences of human, rat, mouse, hamster, chicken, salmon andXenopus HNF-1[alpha], and the structurally-related HNF-1[beta] implying that these residues are functionally important. In addition to showing that each mutation co-segregated with diabetes, we also screened 60 healthy unrelated non-diabetic French subjects (120 chromosomes) for each mutation and have not observed any in this group. As shown in Figure1 , seven of 67 carriers of mutations have normal glucose tolerance at the present time. Six of these are less than 25 years of age and thus still at risk of developing diabetes in the future, and one carrying a missense mutation (Fig.1 , F515-20) is 42 years, suggesting he may indeed be non-penetrant. Thus, mutations inMODY3 are highly but not completely penetrant.


Figure 1. Pedigrees of theMODY families with mutations in the HNF-1[alpha] gene. Individuals with MODY/NIDDM are denoted by black symbols, non-diabetic individuals by open symbols and untested by grey symbols. The presently unaffected individuals carrying a mutation are indicated by shaded symbols. The arrow indicates the individual from each pedigree who was screened for mutations. The HNF1-[alpha] genotype of each individual is indicated below the symbol: N, normal; M, mutant.

DISCUSSION

Mutations in HNF-1[alpha] result in a subtype of MODY characterised by a severe insulin secretory defect. However, little is known about the pathophysiological mechanisms leading to this secretory defect. They might include abnormal pancreatic islet development during foetal life thereby limiting their later function, as well as impaired transcriptional regulation of genes, the identities of which are presently unknown, that play a key role in normal pancreatic beta cell function.

Regarding the clinical profile of MODY3 subjects, one might expect that subjects with frameshift and nonsense mutations may be more severely affected than those with missense mutations. However, there were no apparent differences in the age at onset or severity of diabetes between these two groups of affected subjects (data not shown). More detailed clinical studies might reveal subtle differences between these groups as found in studies of patients with different types of mutations in the glucokinase gene (3 ).

Table 1 .HNF-1[alpha] gene mutations in MODY3 families
Family
 
 

 Location of mutation
Exon

 Nucleotide change
Codon

 Amino acid change
 

 Designation
 
 

  
F159

 4

 292

 Deletion G

 Frameshift

 G292fsdelG
F213

 2

 122

 TAC -> TGC

 Tyr -> Cys

 Y122C
F384

 2

 159

 CGG -> CAG

 Arg -> Gln

 R159Q
F515

 2

 142

 TCC -> TTC

 Ser -> Phe

 S142F
F549

 6

 379

 Insertion C

 Frameshift

 P379fsinsC
F593

 1

 55/56

 Deletion GAGGG

 Frameshift

 R55G56fsdelGAGGG
F632

 6

 379

 Deletion CT

 Frameshift

 P379fsdelCT
F636

 1

 7

 CAG -> TAG

 Gln -> Stop (AM)

 Q7X
F703

 2

 171

 CGA -> TGA

 Arg -> Stop (OP)

 R171X
FS4

 4

 291

 Deletion C

 Frameshift

 P291fsdelC

HNF-1[alpha] is composed of three functional domains: a NH2- terminal dimerisation domain, a DNA binding domain with POU-like and homeodomain-like motifs and a COOH-terminal transactivation domain (Fig.2 ) (15 ). The functional form of HNF-1[alpha] is a dimer, either a homodimer or a heterodimer with HNF-1[beta] (17 ). In liver and pancreas, homodimers are predominant compared to kidney where 50% of the molecules are HNF-1[alpha]/HNF-1[beta] heterodimers. Thus, a heterozygous mutant may lead to a marked decrease of HNF-1[alpha] activity in pancreas and liver with a smaller effect in kidney (18 ). However, the genetic mechanism whereby these heterozygous mutations lead to MODY is not clear; possible mechanisms include a gene dosage effect as in MODY2 (19 ), or a dominant negative effect (20 ). The identification of the Q7X mutation in a MODY family does not support a dominant negative mechanism, at least for this mutation, and is consistent with gene dosage as being the possible mechanism. This mutation results in the expression of a very short protein bearing only six out of the 31 amino acids of the dimerisation domain. It is unlikely that this mutant could bind effectively to the normal HNF-1[alpha] and HNF-1[beta] molecules and exert a dominant negative effect. Interestingly, studies of HNF-1[alpha] deficient transgenic mice support a dominant negative mechanism (18 ). Homozygous animals completely lacking HNF-1[alpha] suffer from phenylketonuria and renal tubular dysfunction with massive glycosuria (up to 10% of their body weight daily). They are mildly hyperglycaemic despite the massive glucosuria, suggesting that they might have an insulin secretory defect. The heterozygous mice seem to be phenotypically normal suggesting that a 50% reduction of HNF-1[alpha], at least in mice, does not necessarily lead to diabetes and kidney abnormalities.


Figure 2. Schematic representation of the structure of HNF1-[alpha] protein showing the different functional domains depicted with hatched boxes. Amino acid residue numbers are indicated in parentheses (see ref. 23). The relative position of mutations associated with synthesis of an abnormal HNF-1[alpha] protein are shown.

In conclusion, HNF-1[alpha] is a major gene for MODY with mutations in this transcription factor being present in 25-50% of French patients with MODY (10 ). Its role in the susceptibility to the more common late-onset NIDDM is less certain. Linkage studies seem to exclude a role as a major susceptibility gene (21 ,22 ) but leave unresolved whether it may have a small effect. Mahtaniet al. recently proposed that mutations inMODY3 might be responsible for diabetes in a subgroup of subjects with late-onset NIDDM characterised by low insulin secretion (22 ). If confirmed, HNF-1[alpha] would be the most common NIDDM susceptibility gene identified to date.

MATERIALS AND METHODS

One affected subject from each of the ten MODY3 families was screened for mutations in the HNF-1[alpha] gene, as described previously (14 ) by PCR amplification of each exon and direct sequencing of the PCR product. The sequence of each mutation was confirmed by cloning the PCR product into the vector pGEMTM-T (Promega, Madison, WI) and sequencing clones representing both alleles. The presence of the specific mutation within each family was assessed by amplifying and directly sequencing the appropriate exon for all the affected and unaffected family members.

ACKNOWLEDGEMENTS

This work was supported by the French Ministry of Research, Pasteur Institute of Lille (France), Centre National de la Recherche Scientifique, Institut National pour la Science et la Recherche Medicale, the European Union (Biomed 2 grant no. BMH4-CT95-0662), the Howard Hughes Medical Institute, Wellcome Trust, U.S. Public Health Service, Juvenile Diabetes Foundation International, Bayer Laboratory France and Institut Lilly France (Contrat de Recherche Lilly-ALFEDIAM).

REFERENCES

1 Fajans, S.S., Bell, G.I., Bowden, D.W., Halter, J.B. and Polonsky, K.S. (1994) Maturity-onset diabetes of the young. Life Sci. 55, 413-422. MEDLINE Abstract

2 Velho, G., Froguel, P., Clment, K., Pueyo, M.E., Rakotoambinina, B., Zouali, H., Passa, P., Cohen, D. and Robert, J.J. (1992) Primary pancreatic beta-cell secretory defect caused by mutations in the glucokinase in kindreds of maturity onset diabetes of the young. Lancet 340, 444-448. MEDLINE Abstract

3 Byrne, M.M., Sturis, J., Clément, K., Vionnet, N., Pueyo, M.E., Stoffel, M., Takeda, J., Passa, P., Cohen, D., Bell, G., Velho, G., Froguel, P. and Polonsky, K.S. (1994) Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J. Clin. Invest. 93, 1120-1130. MEDLINE Abstract

4 Herman, W.H., Fajans, S.S., Ortiz, F.J., Smith, M.J., Sturis, J., Bell, G.I., Polonsky, K.S. and Halter, J.B. (1994) Abnormal insulin secretion, not insulin resistance, is the genetic or primary defect of MODY in the RW pedigree. Diabetes 43, 40-46. MEDLINE Abstract

5 Byrne, M.M., Sturis, J., Fajans, S.S., Ortiz, F.J., Stoltz, A., Stoffel, M., Smith, M.J., Bell, G.I., Halter, J.B. and Polonsky, K.S. (1995) Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 44, 699-704. MEDLINE Abstract

6 Byrne, M.M., Sturis, J., Menzel, S., Yamagata, K., Fajans, S.S., Dronsfield, M.J., Bain, S.C., Hattersley, A.T., Velho, G., Froguel, P., Bell, G.I. and Polonsky, K.S. (1996) Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes mellitus susceptibility gene MODY on chromosome 12. Diabetes 45, 1503-1510. MEDLINE Abstract

7 Froguel, P., Velho, G., Cohen, D. and Passa, P. (1991) Strategies for the collection sibling-pair data for genetic studies in type 2 (non insulin-dependent) diabetes mellitus. Diabetologia 34, 685. MEDLINE Abstract

8 Bell, G.I., Xiang, K.S., Newman, M.V., Wu, S.H., Wright, L.G., Fajans, S.S. and Cox, N.J. (1991) Gene for non insulin dependent diabetes mellitus (maturity onset diabetes of the young subtype) is linked to DNA polymorphism on chromosome 20q. Proc. Natl. Acad. Sci. USA 88, 1484-1488. MEDLINE Abstract

9 Froguel, P., Vaxillaire, M., Sun, F., Velho, G., Zouali, H., Butel, M.O., Lesage, S., Vionnet, N., Clément, K., Fougerousse, F., Tanizawa, Y., Weissenbach, J., Beckmann, J.S., Lathrop, G.M., Passa, P., Permutt, M.A. and Cohen, D. (1992) The glucokinase locus on chromosome 7p is closely linked to early onset non insulin dependent diabetes mellitus. Nature 356, 162-164. MEDLINE Abstract

10 Vaxillaire, M., Boccio, V., Philippi, A., Vigouroux, C., Terwilliger, J., Passa, P., Beckman, J.S., Velho, G., Lathrop, G.M. and Froguel, P. (1995) A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nature Genet. 9, 418-423. MEDLINE Abstract

11 Velho, G., Blanché, H., Vaxillaire, M., Bellanné-Chantelot, C., Pardini, V.C., Timsit, J., Passa, P., Deschamps, I., Robert, J.J., Weber, I.T., Marotta, D., Pilkis, S.J., Lipkind, G.M., Bell, G.I. and Froguel, P. (1997) Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia 40, (in press).

12 Velho, G., Petersen, K.F., Perseghin, G., Hwang, J.-H., Rothman, D.L., Pueyo, M.E., Cline, G.W., Froguel, P. and Shulman, G.I. (1996) Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J. Clin. Invest. 98, 1755-1761. MEDLINE Abstract

13 Velho, G., Vaxillaire, M., Boccio, V., Charpentier, G. and Froguel, P. (1996) Diabetes complications in NIDDM kindreds linked to the MODY-3 locus on chromosome 12q. Diabetes Care 19, 915-919. MEDLINE Abstract

14 Yamagata, K., Oda, N., Kaisaki, P.J., Menzel, S., Furuta, H., Vaxillaire, M., Southam, L., Cox, R.D., Lathrop, G.M., Boriraj, V.V., Chen, X., Cox, N.J., Oda, Y., Yano, H., Le Beau, M.M., Yamada, S., Nishigori, H., Takeda, J., Fajans, S.S., Hattersley, A.T., Iwasaki, N., Hansen, T., Pedersen, O., Polonsky, K.S., Turner, R.C., Velho, G., Chevre, J.C., Froguel, P. and Bell, G.I. (1996) Mutations in the hepatocyte nuclear factor 1 alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455-458. MEDLINE Abstract

15 Tronche, F. and Yaniv, M. (1992) HNF1, a homeoprotein member of the hepatic transcription regulatory network. Bioessays 14, 579-587. MEDLINE Abstract

16 Yamagata, K., Furuta, H., Oda, O., Kaisaki, P.J., Menzel, S., Cox, N.J., Fajans, S.S., Signorini, S., Stoffel, M. and Bell, G.I. (1996) Mutations in the hepatocyte nuclear factor 4 alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458-460. MEDLINE Abstract

17 Rey-Campos, J., Chouard, T., Yaniv, M. and Cereghini, S. (1991) vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1. EMBO J. 10, 1445-1457. MEDLINE Abstract

18 Pontoglio, M., Barra, J., Hadchouel, M., Doyen, A., Kress, C., Poggi Bach, J., Babinet, C. and Yaniv, M. (1996) Hepatocyte Nuclear Factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell 84, 572-585.

19 Gidh-Jain, M., Takeda, J., Xu, L.Z., Lange, A.J., Vionnet, N., Stoffel, M., Froguel, P., Velho, G., Sun, F., Cohen, D., Patel, P., Lo, Y.M.D., Hattersley, A.T., Luthman, H., Wedell, A., Charles, R.S., Harrison, R.W., Weber, I.T., Bell, G.I. and Pilkis, S.J. (1993) Glucokinase mutations associated with non insulin dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc. Natl. Acad. Sci. USA 90, 1932-1936. MEDLINE Abstract

20 Nicosia, A., Tafi, R. and Monaci, P. (1992) Trans-dominant inhibition of transcription activator LFB1. Nucleic Acids Res. 20, 5321-5328. MEDLINE Abstract

21 Lesage, S., Hani, E.H., Philippi, A., Vaxillaire, M., Hager, J., Passa, P., Demenais, F., Froguel, P. and Vionnet, N. (1995) Linkage analyses of the MODY3 locus on chromosome 12q with late-onset NIDDM. Diabetes 44, 1243-1247. MEDLINE Abstract

22 Mahtani, M.M., Widén, E., Lehto, M., Thomas, J., McCarthy, M., Brayer, J., Bryant, B., Chan, G., Daly, M., Forsblom, C., Kanninen, T., Kirby, A., Kruglyak, L., Munnelly, K., Parkkonen, M., Reeve-Daly, M.P., Weaver, A., Brettin, T., Duyk, G., Lander, E.S. and Groop, L.C. (1996) Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nature Genet. 14, 90-94. MEDLINE Abstract

23 Mendel, D.B., Hausen, L.P., Graves, M.K., Conley, B.P. and Crabtree, G.R. (1991) HNF-1[alpha] and HNF-1[beta] (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro. Genes Dev. 5, 1042-1056. MEDLINE Abstract

*To whom correspondence should be addressed

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