Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia
Heterozygous glucokinase (GCK) mutations cause a subtype of maturity-onset diabetes of the young (GCK-MODY). Over 600 GCK mutations have been reported of which ∼65% are missense. In many cases co-segregation has not been established and despite the importance of functional studies in ascribing patho...
Gespeichert in:
| Veröffentlicht in: | PloS one 2012-04, Vol.7 (4), p.e34541-e34541 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | e34541 |
|---|---|
| container_issue | 4 |
| container_start_page | e34541 |
| container_title | PloS one |
| container_volume | 7 |
| creator | Valentínová, Lucia Beer, Nicola L Staník, Juraj Tribble, Nicholas D van de Bunt, Martijn Hučková, Miroslava Barrett, Amy Klimeš, Iwar Gašperíková, Daniela Gloyn, Anna L |
| description | Heterozygous glucokinase (GCK) mutations cause a subtype of maturity-onset diabetes of the young (GCK-MODY). Over 600 GCK mutations have been reported of which ∼65% are missense. In many cases co-segregation has not been established and despite the importance of functional studies in ascribing pathogenicity for missense variants these have only been performed for C, c.1113-1114delGC) were novel. Parental DNA was available for 22 probands (covering 14/22 mutations) and co-segregation established in all cases. Bioinformatic analysis predicted all missense mutations to be damaging. Nine (I110N, V200A, N204D, G223S, G258R, F419S, V244G, L315H, I436N) mutations were functionally evaluated. Basic kinetic analysis explained pathogenicity for 7 mutants which showed reduced glucokinase activity with relative activity indices (RAI) between 0.6 to |
| doi_str_mv | 10.1371/journal.pone.0034541 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1340965668</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A477145453</galeid><doaj_id>oai_doaj_org_article_dcb84374485d4c3eb7c33ea7ba2112e7</doaj_id><sourcerecordid>A477145453</sourcerecordid><originalsourceid>FETCH-LOGICAL-c691t-c82a4455e4d6cb5b2ccd47fa0fbf01c4c1596375e4b227ac79559cceb2b208323</originalsourceid><addsrcrecordid>eNqNk9tu00AQhi0EoqXwBggsIYG4SNiTTzdIVcUhUqVKFLhdjcdrZ9P1bvCuK_ICPDfrJK0S1AvkC3tnvv8fezyTJC8pmVNe0A8rNw4WzHztrJoTwkUm6KPklFaczXJG-OOD55PkmfcrQjJe5vnT5IQxUfGCsNPkz6JRNuhWIwTtbAq2SdvR4nQAk-ISBsCgBu13edem1t0qk3ZmRHejLXiV9mPYZn2KMHptu7SHMA46bGYxqELaaKhVUH6Sh6VKN26MkLbptXG3cKPhefKkBePVi_39LPnx-dP3i6-zy6svi4vzyxnmFQ0zLBkIkWVKNDnWWc0QG1G0QNq6JRQF0qzKeRHzNWMFYFFlWYWoalYzUnLGz5LXO9-1cV7uW-gl5YJUeZbnZSQWO6JxsJLrQfcwbKQDLbcBN3QShqDRKNlgXQpeCFFmjUCu6gI5V1DUwChlqoheH_fVxrpXDcZOD2COTI8zVi9l524l54wSyqPBu73B4H6NygfZa4_KGLDKjV5WFa9IRUsayTf_kA9_3J7qIL6_tq2LZXHylOeiKGicoWyqOn-Ailejeo1x3Fod40eC90eCyAT1O3RxGLxcXH_7f_bq5zH79oBdKjBh6Z0Zt7N2DIodiIPzflDtfY8pkdO23HVDTtsi99sSZa8O_8-96G49-F_1ORLK</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1340965668</pqid></control><display><type>article</type><title>Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><source>Public Library of Science (PLoS)</source><creator>Valentínová, Lucia ; Beer, Nicola L ; Staník, Juraj ; Tribble, Nicholas D ; van de Bunt, Martijn ; Hučková, Miroslava ; Barrett, Amy ; Klimeš, Iwar ; Gašperíková, Daniela ; Gloyn, Anna L</creator><creatorcontrib>Valentínová, Lucia ; Beer, Nicola L ; Staník, Juraj ; Tribble, Nicholas D ; van de Bunt, Martijn ; Hučková, Miroslava ; Barrett, Amy ; Klimeš, Iwar ; Gašperíková, Daniela ; Gloyn, Anna L</creatorcontrib><description><![CDATA[Heterozygous glucokinase (GCK) mutations cause a subtype of maturity-onset diabetes of the young (GCK-MODY). Over 600 GCK mutations have been reported of which ∼65% are missense. In many cases co-segregation has not been established and despite the importance of functional studies in ascribing pathogenicity for missense variants these have only been performed for <10% of mutations. The aim of this study was to determine the minimum prevalence of GCK-MODY amongst diabetic subjects in Slovakia by sequencing GCK in 100 Slovakian probands with a phenotype consistent with GCK-MODY and to explore the pathogenicity of identified variants through family and functional studies. Twenty-two mutations were identified in 36 families (17 missense) of which 7 (I110N, V200A, N204D, G258R, F419S, c.580-2A>C, c.1113-1114delGC) were novel. Parental DNA was available for 22 probands (covering 14/22 mutations) and co-segregation established in all cases. Bioinformatic analysis predicted all missense mutations to be damaging. Nine (I110N, V200A, N204D, G223S, G258R, F419S, V244G, L315H, I436N) mutations were functionally evaluated. Basic kinetic analysis explained pathogenicity for 7 mutants which showed reduced glucokinase activity with relative activity indices (RAI) between 0.6 to <0.001 compared to wild-type GCK (1.0). For the remaining 2 mutants additional molecular mechanisms were investigated. Differences in glucokinase regulatory protein (GKRP) -mediated-inhibition of GCK were observed for both L315H & I436N when compared to wild type (IC(50) 14.6±0.1 mM & 20.3±1.6 mM vs.13.3±0.1 mM respectively [p<0.03]). Protein instability as assessed by thermal lability studies demonstrated that both L315H and I436N show marked thermal instability compared to wild-type GCK (RAI at 55°C 8.8±0.8% & 3.1±0.4% vs. 42.5±3.9% respectively [p<0.001]). The minimum prevalence of GCK-MODY amongst Slovakian patients with diabetes was 0.03%. In conclusion, we have identified 22 GCK mutations in 36 Slovakian probands and demonstrate that combining family, bioinformatic and functional studies can aid the interpretation of variants identified by molecular diagnostic screening.]]></description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0034541</identifier><identifier>PMID: 22493702</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adolescent ; Adult ; Amino acids ; Analysis ; Biology ; Blood proteins ; Child ; Child, Preschool ; Deoxyribonucleic acid ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 2 - diagnosis ; Diabetes Mellitus, Type 2 - genetics ; Diabetics ; Diagnostic systems ; DNA ; DNA Mutational Analysis ; Endocrinology ; Enzyme kinetics ; Enzyme Stability ; Families & family life ; Fasting ; Female ; Gene expression ; Genetic aspects ; Genetic Testing ; Genotype ; Glucokinase ; Glucokinase - genetics ; Glucose ; Heterozygote ; Humans ; Hyperglycemia ; Identification ; Insulin ; Isoenzymes ; Lability ; Male ; Medicine ; Metabolism ; Middle Aged ; Missense mutation ; Molecular modelling ; Mutants ; Mutation ; Mutation, Missense ; Parenting ; Pathogenicity ; Pathogens ; Pedigree ; Phenotype ; Phenotypes ; Science ; Slovakia ; Stability ; Stability analysis ; Studies ; Thermal instability ; Type 2 diabetes</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e34541-e34541</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Valentínová et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Valentínová et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-c82a4455e4d6cb5b2ccd47fa0fbf01c4c1596375e4b227ac79559cceb2b208323</citedby><cites>FETCH-LOGICAL-c691t-c82a4455e4d6cb5b2ccd47fa0fbf01c4c1596375e4b227ac79559cceb2b208323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321013/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321013/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22493702$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Valentínová, Lucia</creatorcontrib><creatorcontrib>Beer, Nicola L</creatorcontrib><creatorcontrib>Staník, Juraj</creatorcontrib><creatorcontrib>Tribble, Nicholas D</creatorcontrib><creatorcontrib>van de Bunt, Martijn</creatorcontrib><creatorcontrib>Hučková, Miroslava</creatorcontrib><creatorcontrib>Barrett, Amy</creatorcontrib><creatorcontrib>Klimeš, Iwar</creatorcontrib><creatorcontrib>Gašperíková, Daniela</creatorcontrib><creatorcontrib>Gloyn, Anna L</creatorcontrib><title>Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia</title><title>PloS one</title><addtitle>PLoS One</addtitle><description><![CDATA[Heterozygous glucokinase (GCK) mutations cause a subtype of maturity-onset diabetes of the young (GCK-MODY). Over 600 GCK mutations have been reported of which ∼65% are missense. In many cases co-segregation has not been established and despite the importance of functional studies in ascribing pathogenicity for missense variants these have only been performed for <10% of mutations. The aim of this study was to determine the minimum prevalence of GCK-MODY amongst diabetic subjects in Slovakia by sequencing GCK in 100 Slovakian probands with a phenotype consistent with GCK-MODY and to explore the pathogenicity of identified variants through family and functional studies. Twenty-two mutations were identified in 36 families (17 missense) of which 7 (I110N, V200A, N204D, G258R, F419S, c.580-2A>C, c.1113-1114delGC) were novel. Parental DNA was available for 22 probands (covering 14/22 mutations) and co-segregation established in all cases. Bioinformatic analysis predicted all missense mutations to be damaging. Nine (I110N, V200A, N204D, G223S, G258R, F419S, V244G, L315H, I436N) mutations were functionally evaluated. Basic kinetic analysis explained pathogenicity for 7 mutants which showed reduced glucokinase activity with relative activity indices (RAI) between 0.6 to <0.001 compared to wild-type GCK (1.0). For the remaining 2 mutants additional molecular mechanisms were investigated. Differences in glucokinase regulatory protein (GKRP) -mediated-inhibition of GCK were observed for both L315H & I436N when compared to wild type (IC(50) 14.6±0.1 mM & 20.3±1.6 mM vs.13.3±0.1 mM respectively [p<0.03]). Protein instability as assessed by thermal lability studies demonstrated that both L315H and I436N show marked thermal instability compared to wild-type GCK (RAI at 55°C 8.8±0.8% & 3.1±0.4% vs. 42.5±3.9% respectively [p<0.001]). The minimum prevalence of GCK-MODY amongst Slovakian patients with diabetes was 0.03%. In conclusion, we have identified 22 GCK mutations in 36 Slovakian probands and demonstrate that combining family, bioinformatic and functional studies can aid the interpretation of variants identified by molecular diagnostic screening.]]></description><subject>Adolescent</subject><subject>Adult</subject><subject>Amino acids</subject><subject>Analysis</subject><subject>Biology</subject><subject>Blood proteins</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Deoxyribonucleic acid</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 2 - diagnosis</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Diabetics</subject><subject>Diagnostic systems</subject><subject>DNA</subject><subject>DNA Mutational Analysis</subject><subject>Endocrinology</subject><subject>Enzyme kinetics</subject><subject>Enzyme Stability</subject><subject>Families & family life</subject><subject>Fasting</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Genetic Testing</subject><subject>Genotype</subject><subject>Glucokinase</subject><subject>Glucokinase - genetics</subject><subject>Glucose</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Hyperglycemia</subject><subject>Identification</subject><subject>Insulin</subject><subject>Isoenzymes</subject><subject>Lability</subject><subject>Male</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Missense mutation</subject><subject>Molecular modelling</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Parenting</subject><subject>Pathogenicity</subject><subject>Pathogens</subject><subject>Pedigree</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Science</subject><subject>Slovakia</subject><subject>Stability</subject><subject>Stability analysis</subject><subject>Studies</subject><subject>Thermal instability</subject><subject>Type 2 diabetes</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tu00AQhi0EoqXwBggsIYG4SNiTTzdIVcUhUqVKFLhdjcdrZ9P1bvCuK_ICPDfrJK0S1AvkC3tnvv8fezyTJC8pmVNe0A8rNw4WzHztrJoTwkUm6KPklFaczXJG-OOD55PkmfcrQjJe5vnT5IQxUfGCsNPkz6JRNuhWIwTtbAq2SdvR4nQAk-ISBsCgBu13edem1t0qk3ZmRHejLXiV9mPYZn2KMHptu7SHMA46bGYxqELaaKhVUH6Sh6VKN26MkLbptXG3cKPhefKkBePVi_39LPnx-dP3i6-zy6svi4vzyxnmFQ0zLBkIkWVKNDnWWc0QG1G0QNq6JRQF0qzKeRHzNWMFYFFlWYWoalYzUnLGz5LXO9-1cV7uW-gl5YJUeZbnZSQWO6JxsJLrQfcwbKQDLbcBN3QShqDRKNlgXQpeCFFmjUCu6gI5V1DUwChlqoheH_fVxrpXDcZOD2COTI8zVi9l524l54wSyqPBu73B4H6NygfZa4_KGLDKjV5WFa9IRUsayTf_kA9_3J7qIL6_tq2LZXHylOeiKGicoWyqOn-Ailejeo1x3Fod40eC90eCyAT1O3RxGLxcXH_7f_bq5zH79oBdKjBh6Z0Zt7N2DIodiIPzflDtfY8pkdO23HVDTtsi99sSZa8O_8-96G49-F_1ORLK</recordid><startdate>20120406</startdate><enddate>20120406</enddate><creator>Valentínová, Lucia</creator><creator>Beer, Nicola L</creator><creator>Staník, Juraj</creator><creator>Tribble, Nicholas D</creator><creator>van de Bunt, Martijn</creator><creator>Hučková, Miroslava</creator><creator>Barrett, Amy</creator><creator>Klimeš, Iwar</creator><creator>Gašperíková, Daniela</creator><creator>Gloyn, Anna L</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120406</creationdate><title>Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia</title><author>Valentínová, Lucia ; Beer, Nicola L ; Staník, Juraj ; Tribble, Nicholas D ; van de Bunt, Martijn ; Hučková, Miroslava ; Barrett, Amy ; Klimeš, Iwar ; Gašperíková, Daniela ; Gloyn, Anna L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-c82a4455e4d6cb5b2ccd47fa0fbf01c4c1596375e4b227ac79559cceb2b208323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Amino acids</topic><topic>Analysis</topic><topic>Biology</topic><topic>Blood proteins</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Deoxyribonucleic acid</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Type 2 - diagnosis</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Diabetics</topic><topic>Diagnostic systems</topic><topic>DNA</topic><topic>DNA Mutational Analysis</topic><topic>Endocrinology</topic><topic>Enzyme kinetics</topic><topic>Enzyme Stability</topic><topic>Families & family life</topic><topic>Fasting</topic><topic>Female</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Genetic Testing</topic><topic>Genotype</topic><topic>Glucokinase</topic><topic>Glucokinase - genetics</topic><topic>Glucose</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Hyperglycemia</topic><topic>Identification</topic><topic>Insulin</topic><topic>Isoenzymes</topic><topic>Lability</topic><topic>Male</topic><topic>Medicine</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Missense mutation</topic><topic>Molecular modelling</topic><topic>Mutants</topic><topic>Mutation</topic><topic>Mutation, Missense</topic><topic>Parenting</topic><topic>Pathogenicity</topic><topic>Pathogens</topic><topic>Pedigree</topic><topic>Phenotype</topic><topic>Phenotypes</topic><topic>Science</topic><topic>Slovakia</topic><topic>Stability</topic><topic>Stability analysis</topic><topic>Studies</topic><topic>Thermal instability</topic><topic>Type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Valentínová, Lucia</creatorcontrib><creatorcontrib>Beer, Nicola L</creatorcontrib><creatorcontrib>Staník, Juraj</creatorcontrib><creatorcontrib>Tribble, Nicholas D</creatorcontrib><creatorcontrib>van de Bunt, Martijn</creatorcontrib><creatorcontrib>Hučková, Miroslava</creatorcontrib><creatorcontrib>Barrett, Amy</creatorcontrib><creatorcontrib>Klimeš, Iwar</creatorcontrib><creatorcontrib>Gašperíková, Daniela</creatorcontrib><creatorcontrib>Gloyn, Anna L</creatorcontrib><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: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</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>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Valentínová, Lucia</au><au>Beer, Nicola L</au><au>Staník, Juraj</au><au>Tribble, Nicholas D</au><au>van de Bunt, Martijn</au><au>Hučková, Miroslava</au><au>Barrett, Amy</au><au>Klimeš, Iwar</au><au>Gašperíková, Daniela</au><au>Gloyn, Anna L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-04-06</date><risdate>2012</risdate><volume>7</volume><issue>4</issue><spage>e34541</spage><epage>e34541</epage><pages>e34541-e34541</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract><![CDATA[Heterozygous glucokinase (GCK) mutations cause a subtype of maturity-onset diabetes of the young (GCK-MODY). Over 600 GCK mutations have been reported of which ∼65% are missense. In many cases co-segregation has not been established and despite the importance of functional studies in ascribing pathogenicity for missense variants these have only been performed for <10% of mutations. The aim of this study was to determine the minimum prevalence of GCK-MODY amongst diabetic subjects in Slovakia by sequencing GCK in 100 Slovakian probands with a phenotype consistent with GCK-MODY and to explore the pathogenicity of identified variants through family and functional studies. Twenty-two mutations were identified in 36 families (17 missense) of which 7 (I110N, V200A, N204D, G258R, F419S, c.580-2A>C, c.1113-1114delGC) were novel. Parental DNA was available for 22 probands (covering 14/22 mutations) and co-segregation established in all cases. Bioinformatic analysis predicted all missense mutations to be damaging. Nine (I110N, V200A, N204D, G223S, G258R, F419S, V244G, L315H, I436N) mutations were functionally evaluated. Basic kinetic analysis explained pathogenicity for 7 mutants which showed reduced glucokinase activity with relative activity indices (RAI) between 0.6 to <0.001 compared to wild-type GCK (1.0). For the remaining 2 mutants additional molecular mechanisms were investigated. Differences in glucokinase regulatory protein (GKRP) -mediated-inhibition of GCK were observed for both L315H & I436N when compared to wild type (IC(50) 14.6±0.1 mM & 20.3±1.6 mM vs.13.3±0.1 mM respectively [p<0.03]). Protein instability as assessed by thermal lability studies demonstrated that both L315H and I436N show marked thermal instability compared to wild-type GCK (RAI at 55°C 8.8±0.8% & 3.1±0.4% vs. 42.5±3.9% respectively [p<0.001]). The minimum prevalence of GCK-MODY amongst Slovakian patients with diabetes was 0.03%. In conclusion, we have identified 22 GCK mutations in 36 Slovakian probands and demonstrate that combining family, bioinformatic and functional studies can aid the interpretation of variants identified by molecular diagnostic screening.]]></abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22493702</pmid><doi>10.1371/journal.pone.0034541</doi><tpages>e34541</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-04, Vol.7 (4), p.e34541-e34541 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1340965668 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adolescent Adult Amino acids Analysis Biology Blood proteins Child Child, Preschool Deoxyribonucleic acid Diabetes Diabetes mellitus Diabetes Mellitus, Type 2 - diagnosis Diabetes Mellitus, Type 2 - genetics Diabetics Diagnostic systems DNA DNA Mutational Analysis Endocrinology Enzyme kinetics Enzyme Stability Families & family life Fasting Female Gene expression Genetic aspects Genetic Testing Genotype Glucokinase Glucokinase - genetics Glucose Heterozygote Humans Hyperglycemia Identification Insulin Isoenzymes Lability Male Medicine Metabolism Middle Aged Missense mutation Molecular modelling Mutants Mutation Mutation, Missense Parenting Pathogenicity Pathogens Pedigree Phenotype Phenotypes Science Slovakia Stability Stability analysis Studies Thermal instability Type 2 diabetes |
| title | Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T17%3A14%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20and%20functional%20characterisation%20of%20novel%20glucokinase%20mutations%20causing%20maturity-onset%20diabetes%20of%20the%20young%20in%20Slovakia&rft.jtitle=PloS%20one&rft.au=Valent%C3%ADnov%C3%A1,%20Lucia&rft.date=2012-04-06&rft.volume=7&rft.issue=4&rft.spage=e34541&rft.epage=e34541&rft.pages=e34541-e34541&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0034541&rft_dat=%3Cgale_plos_%3EA477145453%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1340965668&rft_id=info:pmid/22493702&rft_galeid=A477145453&rft_doaj_id=oai_doaj_org_article_dcb84374485d4c3eb7c33ea7ba2112e7&rfr_iscdi=true |