The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3
The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3 Christine Bellanné-Chantelot 1 , Claire Carette 2 , Jean-Pierre Riveline 3 , René Valéro 4 , Jean-François Gautier 5 , Etienne Larger 6 9 , Yves Reznik 7 ,...
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| creator | BELLANNE-CHANTELOT, Christine CARETTE, Claire LECOMTE, Pierre CHAILLOUS, Lucy LALOI-MICHEFIN, Marie WILHEM, Jean-Marie CUNY, Pierre DURON, Francoise GUERCI, Bruno JEANDIDIER, Nathalie MOSNIER-PUDAR, Helen ASSAYAG, Michel RIVELINE, Jean-Pierre DUBOIS-LAFORGUE, Danièle VELHO, Gilberto TIMSIT, José VALERO, René GAUTIER, Jean-Francois LARGER, Etienne REZNIK, Yves DUCLUZEAU, Pierre-Henri SOLA, Agnès HARTEMANN-HEURTIER, Agnès |
| description | The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3
Christine Bellanné-Chantelot 1 ,
Claire Carette 2 ,
Jean-Pierre Riveline 3 ,
René Valéro 4 ,
Jean-François Gautier 5 ,
Etienne Larger 6 9 ,
Yves Reznik 7 ,
Pierre-Henri Ducluzeau 8 ,
Agnès Sola 9 ,
Agnès Hartemann-Heurtier 10 ,
Pierre Lecomte 11 ,
Lucy Chaillous 12 ,
Marie Laloi-Michelin 13 ,
Jean-Marie Wilhem 14 ,
Pierre Cuny 15 ,
Françoise Duron 16 ,
Bruno Guerci 17 ,
Nathalie Jeandidier 18 ,
Helen Mosnier-Pudar 19 ,
Michel Assayag 20 ,
Danièle Dubois-Laforgue 2 ,
Gilberto Velho 21 and
José Timsit 2
1 Department of Genetics, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris6, Paris, France
2 Department of Immunology and Diabetology, AP-HP Hôpital Cochin, Université René Descartes- Paris5, and Inserm, Research Unit
561, Paris, France
3 Department of Endocrinology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France
4 Department of Nutrition-Metabolic Diseases-Endocrinology, AP-HM CHU de la Timone, Marseille, France
5 Department of Endocrinology, AP-HP Hôpital Saint-Louis, Université Denis Diderot-Paris7, Paris, France
6 Department of Diabetology, AP-HP Hôpital Bichat, Paris, France
7 Department of Endocrinology, CHU Caen, Caen, France
8 Department of Endocrinology, CHU Angers, Angers, France
9 Department of Diabetology, AP-HP Hôpital Hôtel Dieu, Paris, France
10 Department of Diabetology, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris6, Paris, France
11 Department of Endocrinology, CHU Bretonneau, Tours, France
12 Department of Endocrinology, CHU Nantes, Nantes, France
13 Department of Internal Medicine, AP-HP Hôpital Lariboisière, Paris, France
14 Department of Internal Medicine, Centre Hospitalier Saint-Morand, Altkirch, France
15 Department of Diabetology, Hôpital Beauregard, Thionville, France
16 Department of Endocrinology, AP-HP Hôpital Saint-Antoine, Paris, France
17 Department of Diabetology, CHU Nancy, Nancy, France
18 Department of Diabetology, CHU Strasbourg, Strasbourg, France
19 Department of Endocrinology, AP-HP Hôpital Cochin, Université Paris 5, Paris, France
20 Department of Internal Medicine, Centre Hospitalier Compiègne, Compiègne, France
21 Inserm, Research Unit 695, Paris, France
Address correspondence and reprint requests to Christine Bellanné-Chantelot, Département de Génétique, Groupe Hospitalier
Pitié-Salpétrière |
| doi_str_mv | 10.2337/db07-0859 |
| format | Article |
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Christine Bellanné-Chantelot 1 ,
Claire Carette 2 ,
Jean-Pierre Riveline 3 ,
René Valéro 4 ,
Jean-François Gautier 5 ,
Etienne Larger 6 9 ,
Yves Reznik 7 ,
Pierre-Henri Ducluzeau 8 ,
Agnès Sola 9 ,
Agnès Hartemann-Heurtier 10 ,
Pierre Lecomte 11 ,
Lucy Chaillous 12 ,
Marie Laloi-Michelin 13 ,
Jean-Marie Wilhem 14 ,
Pierre Cuny 15 ,
Françoise Duron 16 ,
Bruno Guerci 17 ,
Nathalie Jeandidier 18 ,
Helen Mosnier-Pudar 19 ,
Michel Assayag 20 ,
Danièle Dubois-Laforgue 2 ,
Gilberto Velho 21 and
José Timsit 2
1 Department of Genetics, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris6, Paris, France
2 Department of Immunology and Diabetology, AP-HP Hôpital Cochin, Université René Descartes- Paris5, and Inserm, Research Unit
561, Paris, France
3 Department of Endocrinology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France
4 Department of Nutrition-Metabolic Diseases-Endocrinology, AP-HM CHU de la Timone, Marseille, France
5 Department of Endocrinology, AP-HP Hôpital Saint-Louis, Université Denis Diderot-Paris7, Paris, France
6 Department of Diabetology, AP-HP Hôpital Bichat, Paris, France
7 Department of Endocrinology, CHU Caen, Caen, France
8 Department of Endocrinology, CHU Angers, Angers, France
9 Department of Diabetology, AP-HP Hôpital Hôtel Dieu, Paris, France
10 Department of Diabetology, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris6, Paris, France
11 Department of Endocrinology, CHU Bretonneau, Tours, France
12 Department of Endocrinology, CHU Nantes, Nantes, France
13 Department of Internal Medicine, AP-HP Hôpital Lariboisière, Paris, France
14 Department of Internal Medicine, Centre Hospitalier Saint-Morand, Altkirch, France
15 Department of Diabetology, Hôpital Beauregard, Thionville, France
16 Department of Endocrinology, AP-HP Hôpital Saint-Antoine, Paris, France
17 Department of Diabetology, CHU Nancy, Nancy, France
18 Department of Diabetology, CHU Strasbourg, Strasbourg, France
19 Department of Endocrinology, AP-HP Hôpital Cochin, Université Paris 5, Paris, France
20 Department of Internal Medicine, Centre Hospitalier Compiègne, Compiègne, France
21 Inserm, Research Unit 695, Paris, France
Address correspondence and reprint requests to Christine Bellanné-Chantelot, Département de Génétique, Groupe Hospitalier
Pitié-Salpétrière, Bât 6 rue Lapeyronie, 47/83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: christine.bellanne-chantelot{at}psl.aphp.fr
Abstract
OBJECTIVE— The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental
and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-α ( HNF1A ) gene mutation.
RESEARCH DESIGN AND METHODS— We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations
between the genotype and age at diagnosis of diabetes.
RESULTS— Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant
in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three
HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations
(18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis
than those affecting the transactivation domain (20 vs. 30 years, P = 10 −4 ). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations
involving one or two isoforms ( P = 0.03).
CONCLUSIONS— These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and
the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.
HNF1A, hepatocyte nuclear factor 1-α
MODY, maturity-onset diabetes of the young
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 14 November 2007. DOI: 10.2337/db07-0859.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0859 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted November 7, 2007.
Received June 26, 2007.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db07-0859</identifier><identifier>PMID: 18003757</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Adolescent ; Adult ; Age ; Age of Onset ; Aged ; Alternative Splicing ; Amino Acid Substitution ; Amino acids ; Binding Sites ; Biological and medical sciences ; Child ; Child, Preschool ; Demographic aspects ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 2 - genetics ; Diabetes. Impaired glucose tolerance ; Diagnosis ; DNA binding proteins ; DNA Mutational Analysis ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Exons ; Gene mutation ; Gene mutations ; Genetic aspects ; Genetic testing ; Genetic Variation ; Hepatocyte Nuclear Factor 1-alpha - genetics ; Humans ; Insulin ; Life Sciences ; Medical sciences ; Middle Aged ; Mutation ; Mutation, Missense ; Research design ; Sequence Deletion</subject><ispartof>Diabetes (New York, N.Y.), 2008-02, Vol.57 (2), p.503-508</ispartof><rights>2008 INIST-CNRS</rights><rights>COPYRIGHT 2008 American Diabetes Association</rights><rights>Copyright American Diabetes Association Feb 2008</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c624t-f2672895e89f5902d315e8df183553ad2290eb7a54ef929575aa29c347f58b953</citedby><cites>FETCH-LOGICAL-c624t-f2672895e89f5902d315e8df183553ad2290eb7a54ef929575aa29c347f58b953</cites><orcidid>0000-0001-8415-6771 ; 0000-0002-1017-1845 ; 0000-0002-2176-3280 ; 0000-0002-8175-0369 ; 0000-0002-6211-464X ; 0000-0001-7991-0741</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20181233$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18003757$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://univ-angers.hal.science/hal-03275383$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>BELLANNE-CHANTELOT, Christine</creatorcontrib><creatorcontrib>CARETTE, Claire</creatorcontrib><creatorcontrib>LECOMTE, Pierre</creatorcontrib><creatorcontrib>CHAILLOUS, Lucy</creatorcontrib><creatorcontrib>LALOI-MICHEFIN, Marie</creatorcontrib><creatorcontrib>WILHEM, Jean-Marie</creatorcontrib><creatorcontrib>CUNY, Pierre</creatorcontrib><creatorcontrib>DURON, Francoise</creatorcontrib><creatorcontrib>GUERCI, Bruno</creatorcontrib><creatorcontrib>JEANDIDIER, Nathalie</creatorcontrib><creatorcontrib>MOSNIER-PUDAR, Helen</creatorcontrib><creatorcontrib>ASSAYAG, Michel</creatorcontrib><creatorcontrib>RIVELINE, Jean-Pierre</creatorcontrib><creatorcontrib>DUBOIS-LAFORGUE, Danièle</creatorcontrib><creatorcontrib>VELHO, Gilberto</creatorcontrib><creatorcontrib>TIMSIT, José</creatorcontrib><creatorcontrib>VALERO, René</creatorcontrib><creatorcontrib>GAUTIER, Jean-Francois</creatorcontrib><creatorcontrib>LARGER, Etienne</creatorcontrib><creatorcontrib>REZNIK, Yves</creatorcontrib><creatorcontrib>DUCLUZEAU, Pierre-Henri</creatorcontrib><creatorcontrib>SOLA, Agnès</creatorcontrib><creatorcontrib>HARTEMANN-HEURTIER, Agnès</creatorcontrib><title>The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3
Christine Bellanné-Chantelot 1 ,
Claire Carette 2 ,
Jean-Pierre Riveline 3 ,
René Valéro 4 ,
Jean-François Gautier 5 ,
Etienne Larger 6 9 ,
Yves Reznik 7 ,
Pierre-Henri Ducluzeau 8 ,
Agnès Sola 9 ,
Agnès Hartemann-Heurtier 10 ,
Pierre Lecomte 11 ,
Lucy Chaillous 12 ,
Marie Laloi-Michelin 13 ,
Jean-Marie Wilhem 14 ,
Pierre Cuny 15 ,
Françoise Duron 16 ,
Bruno Guerci 17 ,
Nathalie Jeandidier 18 ,
Helen Mosnier-Pudar 19 ,
Michel Assayag 20 ,
Danièle Dubois-Laforgue 2 ,
Gilberto Velho 21 and
José Timsit 2
1 Department of Genetics, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris6, Paris, France
2 Department of Immunology and Diabetology, AP-HP Hôpital Cochin, Université René Descartes- Paris5, and Inserm, Research Unit
561, Paris, France
3 Department of Endocrinology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France
4 Department of Nutrition-Metabolic Diseases-Endocrinology, AP-HM CHU de la Timone, Marseille, France
5 Department of Endocrinology, AP-HP Hôpital Saint-Louis, Université Denis Diderot-Paris7, Paris, France
6 Department of Diabetology, AP-HP Hôpital Bichat, Paris, France
7 Department of Endocrinology, CHU Caen, Caen, France
8 Department of Endocrinology, CHU Angers, Angers, France
9 Department of Diabetology, AP-HP Hôpital Hôtel Dieu, Paris, France
10 Department of Diabetology, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris6, Paris, France
11 Department of Endocrinology, CHU Bretonneau, Tours, France
12 Department of Endocrinology, CHU Nantes, Nantes, France
13 Department of Internal Medicine, AP-HP Hôpital Lariboisière, Paris, France
14 Department of Internal Medicine, Centre Hospitalier Saint-Morand, Altkirch, France
15 Department of Diabetology, Hôpital Beauregard, Thionville, France
16 Department of Endocrinology, AP-HP Hôpital Saint-Antoine, Paris, France
17 Department of Diabetology, CHU Nancy, Nancy, France
18 Department of Diabetology, CHU Strasbourg, Strasbourg, France
19 Department of Endocrinology, AP-HP Hôpital Cochin, Université Paris 5, Paris, France
20 Department of Internal Medicine, Centre Hospitalier Compiègne, Compiègne, France
21 Inserm, Research Unit 695, Paris, France
Address correspondence and reprint requests to Christine Bellanné-Chantelot, Département de Génétique, Groupe Hospitalier
Pitié-Salpétrière, Bât 6 rue Lapeyronie, 47/83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: christine.bellanne-chantelot{at}psl.aphp.fr
Abstract
OBJECTIVE— The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental
and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-α ( HNF1A ) gene mutation.
RESEARCH DESIGN AND METHODS— We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations
between the genotype and age at diagnosis of diabetes.
RESULTS— Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant
in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three
HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations
(18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis
than those affecting the transactivation domain (20 vs. 30 years, P = 10 −4 ). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations
involving one or two isoforms ( P = 0.03).
CONCLUSIONS— These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and
the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.
HNF1A, hepatocyte nuclear factor 1-α
MODY, maturity-onset diabetes of the young
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 14 November 2007. DOI: 10.2337/db07-0859.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0859 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted November 7, 2007.
Received June 26, 2007.
DIABETES</description><subject>Adolescent</subject><subject>Adult</subject><subject>Age</subject><subject>Age of Onset</subject><subject>Aged</subject><subject>Alternative Splicing</subject><subject>Amino Acid Substitution</subject><subject>Amino acids</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Demographic aspects</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Diagnosis</subject><subject>DNA binding proteins</subject><subject>DNA Mutational Analysis</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Exons</subject><subject>Gene mutation</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>Genetic testing</subject><subject>Genetic Variation</subject><subject>Hepatocyte Nuclear Factor 1-alpha - genetics</subject><subject>Humans</subject><subject>Insulin</subject><subject>Life Sciences</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Research design</subject><subject>Sequence Deletion</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqF0l9v0zAQAPAIgdgYPPAFkIUEokgZ_hPX9mPVsQ2ppXsoEnuy3OSSekrtEjuMfQs-Mg6tNg1VQn6IffrdWTlflr0m-JQyJj5VKyxyLLl6kh0TxVTOqPj-NDvGmNCcCCWOshch3GCMx2k9z46IxJgJLo6z38s1oOXdFpBxFYrpcOWDjdY75Gt0-fWcTNC8j-ZvZO6rvjUR0KRJPqIzaxqXeBhsOqwgQkDWoavkwcWAbm1co7mJfWfjXb5wAeIDTEnDhde-dw36MF-cXY9y9jJ7Vps2wKv99yT7dv55Ob3MZ4uLL9PJLC_HtIh5TceCSsVBqporTCtG0r6qiWScM1NRqjCshOEF1IoqLrgxVJWsEDWXK8XZSTba1V2bVm87uzHdnfbG6svJTA8xnJrImWQ_SbLvd3bb-R89hKg3NpTQtsaB74MWmBapn_K_kGKJlRiLBN_-A29837n0w5qScSGpZAPKd6gxLWjrah87UzbgoDOtd1DbFJ4QIQUpCC6SPz3g06pgY8uDCaNHCclE-BUb04eg5cXssc0P2dK3LTSg09tMFwdrl50PoYP6vskE62Fq9TC1epjaZN_su9GvNlA9yP2YJvBuD0woTVt3xpU23DuKiSSpZnIf949qm_Wt7UBX-2F72HChqeaYsT_kPfwL</recordid><startdate>20080201</startdate><enddate>20080201</enddate><creator>BELLANNE-CHANTELOT, Christine</creator><creator>CARETTE, Claire</creator><creator>LECOMTE, Pierre</creator><creator>CHAILLOUS, Lucy</creator><creator>LALOI-MICHEFIN, Marie</creator><creator>WILHEM, Jean-Marie</creator><creator>CUNY, Pierre</creator><creator>DURON, Francoise</creator><creator>GUERCI, Bruno</creator><creator>JEANDIDIER, Nathalie</creator><creator>MOSNIER-PUDAR, Helen</creator><creator>ASSAYAG, Michel</creator><creator>RIVELINE, Jean-Pierre</creator><creator>DUBOIS-LAFORGUE, Danièle</creator><creator>VELHO, Gilberto</creator><creator>TIMSIT, José</creator><creator>VALERO, René</creator><creator>GAUTIER, Jean-Francois</creator><creator>LARGER, Etienne</creator><creator>REZNIK, Yves</creator><creator>DUCLUZEAU, Pierre-Henri</creator><creator>SOLA, Agnès</creator><creator>HARTEMANN-HEURTIER, Agnès</creator><general>American Diabetes Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8GL</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0001-8415-6771</orcidid><orcidid>https://orcid.org/0000-0002-1017-1845</orcidid><orcidid>https://orcid.org/0000-0002-2176-3280</orcidid><orcidid>https://orcid.org/0000-0002-8175-0369</orcidid><orcidid>https://orcid.org/0000-0002-6211-464X</orcidid><orcidid>https://orcid.org/0000-0001-7991-0741</orcidid></search><sort><creationdate>20080201</creationdate><title>The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3</title><author>BELLANNE-CHANTELOT, Christine ; CARETTE, Claire ; LECOMTE, Pierre ; CHAILLOUS, Lucy ; LALOI-MICHEFIN, Marie ; WILHEM, Jean-Marie ; CUNY, Pierre ; DURON, Francoise ; GUERCI, Bruno ; JEANDIDIER, Nathalie ; MOSNIER-PUDAR, Helen ; ASSAYAG, Michel ; RIVELINE, Jean-Pierre ; DUBOIS-LAFORGUE, Danièle ; VELHO, Gilberto ; TIMSIT, José ; VALERO, René ; GAUTIER, Jean-Francois ; LARGER, Etienne ; REZNIK, Yves ; DUCLUZEAU, Pierre-Henri ; SOLA, Agnès ; HARTEMANN-HEURTIER, Agnès</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c624t-f2672895e89f5902d315e8df183553ad2290eb7a54ef929575aa29c347f58b953</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Age</topic><topic>Age of Onset</topic><topic>Aged</topic><topic>Alternative Splicing</topic><topic>Amino Acid Substitution</topic><topic>Amino acids</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Demographic aspects</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Diagnosis</topic><topic>DNA binding proteins</topic><topic>DNA Mutational Analysis</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Exons</topic><topic>Gene mutation</topic><topic>Gene mutations</topic><topic>Genetic aspects</topic><topic>Genetic testing</topic><topic>Genetic Variation</topic><topic>Hepatocyte Nuclear Factor 1-alpha - genetics</topic><topic>Humans</topic><topic>Insulin</topic><topic>Life Sciences</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Mutation, Missense</topic><topic>Research design</topic><topic>Sequence Deletion</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>BELLANNE-CHANTELOT, Christine</creatorcontrib><creatorcontrib>CARETTE, Claire</creatorcontrib><creatorcontrib>LECOMTE, Pierre</creatorcontrib><creatorcontrib>CHAILLOUS, Lucy</creatorcontrib><creatorcontrib>LALOI-MICHEFIN, Marie</creatorcontrib><creatorcontrib>WILHEM, Jean-Marie</creatorcontrib><creatorcontrib>CUNY, Pierre</creatorcontrib><creatorcontrib>DURON, Francoise</creatorcontrib><creatorcontrib>GUERCI, Bruno</creatorcontrib><creatorcontrib>JEANDIDIER, Nathalie</creatorcontrib><creatorcontrib>MOSNIER-PUDAR, Helen</creatorcontrib><creatorcontrib>ASSAYAG, Michel</creatorcontrib><creatorcontrib>RIVELINE, Jean-Pierre</creatorcontrib><creatorcontrib>DUBOIS-LAFORGUE, Danièle</creatorcontrib><creatorcontrib>VELHO, Gilberto</creatorcontrib><creatorcontrib>TIMSIT, José</creatorcontrib><creatorcontrib>VALERO, René</creatorcontrib><creatorcontrib>GAUTIER, Jean-Francois</creatorcontrib><creatorcontrib>LARGER, Etienne</creatorcontrib><creatorcontrib>REZNIK, Yves</creatorcontrib><creatorcontrib>DUCLUZEAU, Pierre-Henri</creatorcontrib><creatorcontrib>SOLA, Agnès</creatorcontrib><creatorcontrib>HARTEMANN-HEURTIER, Agnès</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: High School</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>BELLANNE-CHANTELOT, Christine</au><au>CARETTE, Claire</au><au>LECOMTE, Pierre</au><au>CHAILLOUS, Lucy</au><au>LALOI-MICHEFIN, Marie</au><au>WILHEM, Jean-Marie</au><au>CUNY, Pierre</au><au>DURON, Francoise</au><au>GUERCI, Bruno</au><au>JEANDIDIER, Nathalie</au><au>MOSNIER-PUDAR, Helen</au><au>ASSAYAG, Michel</au><au>RIVELINE, Jean-Pierre</au><au>DUBOIS-LAFORGUE, Danièle</au><au>VELHO, Gilberto</au><au>TIMSIT, José</au><au>VALERO, René</au><au>GAUTIER, Jean-Francois</au><au>LARGER, Etienne</au><au>REZNIK, Yves</au><au>DUCLUZEAU, Pierre-Henri</au><au>SOLA, Agnès</au><au>HARTEMANN-HEURTIER, Agnès</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2008-02-01</date><risdate>2008</risdate><volume>57</volume><issue>2</issue><spage>503</spage><epage>508</epage><pages>503-508</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3
Christine Bellanné-Chantelot 1 ,
Claire Carette 2 ,
Jean-Pierre Riveline 3 ,
René Valéro 4 ,
Jean-François Gautier 5 ,
Etienne Larger 6 9 ,
Yves Reznik 7 ,
Pierre-Henri Ducluzeau 8 ,
Agnès Sola 9 ,
Agnès Hartemann-Heurtier 10 ,
Pierre Lecomte 11 ,
Lucy Chaillous 12 ,
Marie Laloi-Michelin 13 ,
Jean-Marie Wilhem 14 ,
Pierre Cuny 15 ,
Françoise Duron 16 ,
Bruno Guerci 17 ,
Nathalie Jeandidier 18 ,
Helen Mosnier-Pudar 19 ,
Michel Assayag 20 ,
Danièle Dubois-Laforgue 2 ,
Gilberto Velho 21 and
José Timsit 2
1 Department of Genetics, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris6, Paris, France
2 Department of Immunology and Diabetology, AP-HP Hôpital Cochin, Université René Descartes- Paris5, and Inserm, Research Unit
561, Paris, France
3 Department of Endocrinology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France
4 Department of Nutrition-Metabolic Diseases-Endocrinology, AP-HM CHU de la Timone, Marseille, France
5 Department of Endocrinology, AP-HP Hôpital Saint-Louis, Université Denis Diderot-Paris7, Paris, France
6 Department of Diabetology, AP-HP Hôpital Bichat, Paris, France
7 Department of Endocrinology, CHU Caen, Caen, France
8 Department of Endocrinology, CHU Angers, Angers, France
9 Department of Diabetology, AP-HP Hôpital Hôtel Dieu, Paris, France
10 Department of Diabetology, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris6, Paris, France
11 Department of Endocrinology, CHU Bretonneau, Tours, France
12 Department of Endocrinology, CHU Nantes, Nantes, France
13 Department of Internal Medicine, AP-HP Hôpital Lariboisière, Paris, France
14 Department of Internal Medicine, Centre Hospitalier Saint-Morand, Altkirch, France
15 Department of Diabetology, Hôpital Beauregard, Thionville, France
16 Department of Endocrinology, AP-HP Hôpital Saint-Antoine, Paris, France
17 Department of Diabetology, CHU Nancy, Nancy, France
18 Department of Diabetology, CHU Strasbourg, Strasbourg, France
19 Department of Endocrinology, AP-HP Hôpital Cochin, Université Paris 5, Paris, France
20 Department of Internal Medicine, Centre Hospitalier Compiègne, Compiègne, France
21 Inserm, Research Unit 695, Paris, France
Address correspondence and reprint requests to Christine Bellanné-Chantelot, Département de Génétique, Groupe Hospitalier
Pitié-Salpétrière, Bât 6 rue Lapeyronie, 47/83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: christine.bellanne-chantelot{at}psl.aphp.fr
Abstract
OBJECTIVE— The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental
and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-α ( HNF1A ) gene mutation.
RESEARCH DESIGN AND METHODS— We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations
between the genotype and age at diagnosis of diabetes.
RESULTS— Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant
in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three
HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations
(18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis
than those affecting the transactivation domain (20 vs. 30 years, P = 10 −4 ). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations
involving one or two isoforms ( P = 0.03).
CONCLUSIONS— These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and
the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.
HNF1A, hepatocyte nuclear factor 1-α
MODY, maturity-onset diabetes of the young
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 14 November 2007. DOI: 10.2337/db07-0859.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0859 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted November 7, 2007.
Received June 26, 2007.
DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>18003757</pmid><doi>10.2337/db07-0859</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0001-8415-6771</orcidid><orcidid>https://orcid.org/0000-0002-1017-1845</orcidid><orcidid>https://orcid.org/0000-0002-2176-3280</orcidid><orcidid>https://orcid.org/0000-0002-8175-0369</orcidid><orcidid>https://orcid.org/0000-0002-6211-464X</orcidid><orcidid>https://orcid.org/0000-0001-7991-0741</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2008-02, Vol.57 (2), p.503-508 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_gale_incontextcollege_GICCO_A178714104 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adolescent Adult Age Age of Onset Aged Alternative Splicing Amino Acid Substitution Amino acids Binding Sites Biological and medical sciences Child Child, Preschool Demographic aspects Diabetes Diabetes mellitus Diabetes Mellitus, Type 2 - genetics Diabetes. Impaired glucose tolerance Diagnosis DNA binding proteins DNA Mutational Analysis Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Exons Gene mutation Gene mutations Genetic aspects Genetic testing Genetic Variation Hepatocyte Nuclear Factor 1-alpha - genetics Humans Insulin Life Sciences Medical sciences Middle Aged Mutation Mutation, Missense Research design Sequence Deletion |
| title | The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3 |
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