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A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion
Monogenic diabetes is a rare type of diabetes resulting from mutations in a single gene. To date, most cases remain genetically unexplained, posing a challenge for accurate diabetes treatment, which leads to on a molecular diagnosis. Therefore, a trio exome scan was performed in a lean, nonsyndromic...
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| Published in: | Molecular genetics and genomics : MGG 2020-09, Vol.295 (5), p.1253-1262 |
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| container_end_page | 1262 |
| container_issue | 5 |
| container_start_page | 1253 |
| container_title | Molecular genetics and genomics : MGG |
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| creator | Alhaidan, Yazeid Christesen, Henrik Thybo Højlund, Kurt Al Balwi, Mohammed A. Brusgaard, Klaus |
| description | Monogenic diabetes is a rare type of diabetes resulting from mutations in a single gene. To date, most cases remain genetically unexplained, posing a challenge for accurate diabetes treatment, which leads to on a molecular diagnosis. Therefore, a trio exome scan was performed in a lean, nonsyndromic Caucasian girl with diabetes onset at 2½ years who was negative for autoantibodies. The lean father had diabetes from age 11 years. A novel heterozygous mutation in
EDEM2
, c.1271G > A; p.Arg424His, was found in the proband and father. Downregulation of
Edem2
in rat RIN-m β-cells resulted in a decrease in insulin genes
Ins1
to 67.9% (
p
= 0.006) and
Ins2
to 16.8% (
p
|
| doi_str_mv | 10.1007/s00438-020-01695-5 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2415297898</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2428285254</sourcerecordid><originalsourceid>FETCH-LOGICAL-c352t-6c5f2ba890613a48fb4a5b43090903a8c9be88ce384da94bf2d8547fa71a4c53</originalsourceid><addsrcrecordid>eNp9kU9vEzEQxVeISpTCF-BkiQsHFvx318stSgOtlKqV2gM3y2vPpq4cO3g2iH4AvjcOQSBxqOYwc_i9N096TfOG0Q-M0v4jUiqFbimnLWXdoFr1rDllHetb2XHx_O_N1IvmJeIDpazveH_a_FyQlL9DJBtIQEIiYEt8JO4-RH-fsyc-2BFmwE9kdb664gRDhORC2hAProBFQHK7XvIFJzZ5cvP1nBH4sSuAGHJ6TyJYf6DnTMJ2Z0MBX9_gPtZfeHCYK_aqOZlsRHj9Z581d59Xd8uLdn395XK5WLdOKD63nVMTH60eaMeElXoapVWjFHSoI6x2wwhaOxBaejvIceJeK9lPtmdWOiXOmndH213J3_aAs9kGdBCjTZD3aLhkig-9HnRF3_6HPuR9STVcpbjmWnElK8WPlCsZscBkdiVsbXk0jJpDMeZYjKnFmN_FmEMKcRRhhdMGyj_rJ1S_AEL2j_Q</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2428285254</pqid></control><display><type>article</type><title>A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion</title><source>Springer Nature</source><creator>Alhaidan, Yazeid ; Christesen, Henrik Thybo ; Højlund, Kurt ; Al Balwi, Mohammed A. ; Brusgaard, Klaus</creator><creatorcontrib>Alhaidan, Yazeid ; Christesen, Henrik Thybo ; Højlund, Kurt ; Al Balwi, Mohammed A. ; Brusgaard, Klaus</creatorcontrib><description>Monogenic diabetes is a rare type of diabetes resulting from mutations in a single gene. To date, most cases remain genetically unexplained, posing a challenge for accurate diabetes treatment, which leads to on a molecular diagnosis. Therefore, a trio exome scan was performed in a lean, nonsyndromic Caucasian girl with diabetes onset at 2½ years who was negative for autoantibodies. The lean father had diabetes from age 11 years. A novel heterozygous mutation in
EDEM2
, c.1271G > A; p.Arg424His, was found in the proband and father. Downregulation of
Edem2
in rat RIN-m β-cells resulted in a decrease in insulin genes
Ins1
to 67.9% (
p
= 0.006) and
Ins2
to 16.8% (
p
< 0.001) and reduced insulin secretion by 60.4% (
p
= 0.0003). Real-time PCR revealed a major disruption of endocrine pancreas-specific genes, including
Glut2
and
Pxd1
, with mRNA suppression to 54% (
p
< 0.001) and 85.7% (
p
= 0.01), respectively. No other expression changes related to stress or apoptotic genes were observed. Extended clinical follow-up involving ten family members showed that two healthy individuals carried the same mutation with no sign of diabetes in the clinical screen except for a slight increase in IA-2 antibody in one of them, suggesting incomplete penetrance. In conclusion, we describe
EDEM2
as a likely/potential novel diabetes gene, in which inhibition in vitro reduces the expression of β-cell genes involved in the glucose‐stimulated insulin secretion (GSIS) pathway, leading to an overall suppression of insulin secretion but not apoptosis.</description><identifier>ISSN: 1617-4615</identifier><identifier>EISSN: 1617-4623</identifier><identifier>DOI: 10.1007/s00438-020-01695-5</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animal Genetics and Genomics ; Apoptosis ; Autoantibodies ; Beta cells ; Biochemistry ; Biomedical and Life Sciences ; Childhood ; Children ; Diabetes ; Diabetes mellitus ; Genes ; Glucose transporter ; Human Genetics ; Insulin ; Insulin secretion ; Life Sciences ; Microbial Genetics and Genomics ; mRNA ; Mutation ; Original Article ; Pancreas ; Plant Genetics and Genomics ; Secretion</subject><ispartof>Molecular genetics and genomics : MGG, 2020-09, Vol.295 (5), p.1253-1262</ispartof><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2020</rights><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c352t-6c5f2ba890613a48fb4a5b43090903a8c9be88ce384da94bf2d8547fa71a4c53</citedby><cites>FETCH-LOGICAL-c352t-6c5f2ba890613a48fb4a5b43090903a8c9be88ce384da94bf2d8547fa71a4c53</cites><orcidid>0000-0002-0569-2988</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids></links><search><creatorcontrib>Alhaidan, Yazeid</creatorcontrib><creatorcontrib>Christesen, Henrik Thybo</creatorcontrib><creatorcontrib>Højlund, Kurt</creatorcontrib><creatorcontrib>Al Balwi, Mohammed A.</creatorcontrib><creatorcontrib>Brusgaard, Klaus</creatorcontrib><title>A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion</title><title>Molecular genetics and genomics : MGG</title><addtitle>Mol Genet Genomics</addtitle><description>Monogenic diabetes is a rare type of diabetes resulting from mutations in a single gene. To date, most cases remain genetically unexplained, posing a challenge for accurate diabetes treatment, which leads to on a molecular diagnosis. Therefore, a trio exome scan was performed in a lean, nonsyndromic Caucasian girl with diabetes onset at 2½ years who was negative for autoantibodies. The lean father had diabetes from age 11 years. A novel heterozygous mutation in
EDEM2
, c.1271G > A; p.Arg424His, was found in the proband and father. Downregulation of
Edem2
in rat RIN-m β-cells resulted in a decrease in insulin genes
Ins1
to 67.9% (
p
= 0.006) and
Ins2
to 16.8% (
p
< 0.001) and reduced insulin secretion by 60.4% (
p
= 0.0003). Real-time PCR revealed a major disruption of endocrine pancreas-specific genes, including
Glut2
and
Pxd1
, with mRNA suppression to 54% (
p
< 0.001) and 85.7% (
p
= 0.01), respectively. No other expression changes related to stress or apoptotic genes were observed. Extended clinical follow-up involving ten family members showed that two healthy individuals carried the same mutation with no sign of diabetes in the clinical screen except for a slight increase in IA-2 antibody in one of them, suggesting incomplete penetrance. In conclusion, we describe
EDEM2
as a likely/potential novel diabetes gene, in which inhibition in vitro reduces the expression of β-cell genes involved in the glucose‐stimulated insulin secretion (GSIS) pathway, leading to an overall suppression of insulin secretion but not apoptosis.</description><subject>Animal Genetics and Genomics</subject><subject>Apoptosis</subject><subject>Autoantibodies</subject><subject>Beta cells</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Childhood</subject><subject>Children</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Genes</subject><subject>Glucose transporter</subject><subject>Human Genetics</subject><subject>Insulin</subject><subject>Insulin secretion</subject><subject>Life Sciences</subject><subject>Microbial Genetics and Genomics</subject><subject>mRNA</subject><subject>Mutation</subject><subject>Original Article</subject><subject>Pancreas</subject><subject>Plant Genetics and Genomics</subject><subject>Secretion</subject><issn>1617-4615</issn><issn>1617-4623</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kU9vEzEQxVeISpTCF-BkiQsHFvx318stSgOtlKqV2gM3y2vPpq4cO3g2iH4AvjcOQSBxqOYwc_i9N096TfOG0Q-M0v4jUiqFbimnLWXdoFr1rDllHetb2XHx_O_N1IvmJeIDpazveH_a_FyQlL9DJBtIQEIiYEt8JO4-RH-fsyc-2BFmwE9kdb664gRDhORC2hAProBFQHK7XvIFJzZ5cvP1nBH4sSuAGHJ6TyJYf6DnTMJ2Z0MBX9_gPtZfeHCYK_aqOZlsRHj9Z581d59Xd8uLdn395XK5WLdOKD63nVMTH60eaMeElXoapVWjFHSoI6x2wwhaOxBaejvIceJeK9lPtmdWOiXOmndH213J3_aAs9kGdBCjTZD3aLhkig-9HnRF3_6HPuR9STVcpbjmWnElK8WPlCsZscBkdiVsbXk0jJpDMeZYjKnFmN_FmEMKcRRhhdMGyj_rJ1S_AEL2j_Q</recordid><startdate>20200901</startdate><enddate>20200901</enddate><creator>Alhaidan, Yazeid</creator><creator>Christesen, Henrik Thybo</creator><creator>Højlund, Kurt</creator><creator>Al Balwi, Mohammed A.</creator><creator>Brusgaard, Klaus</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-0569-2988</orcidid></search><sort><creationdate>20200901</creationdate><title>A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion</title><author>Alhaidan, Yazeid ; Christesen, Henrik Thybo ; Højlund, Kurt ; Al Balwi, Mohammed A. ; Brusgaard, Klaus</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c352t-6c5f2ba890613a48fb4a5b43090903a8c9be88ce384da94bf2d8547fa71a4c53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animal Genetics and Genomics</topic><topic>Apoptosis</topic><topic>Autoantibodies</topic><topic>Beta cells</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Childhood</topic><topic>Children</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Genes</topic><topic>Glucose transporter</topic><topic>Human Genetics</topic><topic>Insulin</topic><topic>Insulin secretion</topic><topic>Life Sciences</topic><topic>Microbial Genetics and Genomics</topic><topic>mRNA</topic><topic>Mutation</topic><topic>Original Article</topic><topic>Pancreas</topic><topic>Plant Genetics and Genomics</topic><topic>Secretion</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Alhaidan, Yazeid</creatorcontrib><creatorcontrib>Christesen, Henrik Thybo</creatorcontrib><creatorcontrib>Højlund, Kurt</creatorcontrib><creatorcontrib>Al Balwi, Mohammed A.</creatorcontrib><creatorcontrib>Brusgaard, Klaus</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research 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>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</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>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>ProQuest Biological Science Journals</collection><collection>Biotechnology and BioEngineering Abstracts</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>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular genetics and genomics : MGG</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alhaidan, Yazeid</au><au>Christesen, Henrik Thybo</au><au>Højlund, Kurt</au><au>Al Balwi, Mohammed A.</au><au>Brusgaard, Klaus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion</atitle><jtitle>Molecular genetics and genomics : MGG</jtitle><stitle>Mol Genet Genomics</stitle><date>2020-09-01</date><risdate>2020</risdate><volume>295</volume><issue>5</issue><spage>1253</spage><epage>1262</epage><pages>1253-1262</pages><issn>1617-4615</issn><eissn>1617-4623</eissn><abstract>Monogenic diabetes is a rare type of diabetes resulting from mutations in a single gene. To date, most cases remain genetically unexplained, posing a challenge for accurate diabetes treatment, which leads to on a molecular diagnosis. Therefore, a trio exome scan was performed in a lean, nonsyndromic Caucasian girl with diabetes onset at 2½ years who was negative for autoantibodies. The lean father had diabetes from age 11 years. A novel heterozygous mutation in
EDEM2
, c.1271G > A; p.Arg424His, was found in the proband and father. Downregulation of
Edem2
in rat RIN-m β-cells resulted in a decrease in insulin genes
Ins1
to 67.9% (
p
= 0.006) and
Ins2
to 16.8% (
p
< 0.001) and reduced insulin secretion by 60.4% (
p
= 0.0003). Real-time PCR revealed a major disruption of endocrine pancreas-specific genes, including
Glut2
and
Pxd1
, with mRNA suppression to 54% (
p
< 0.001) and 85.7% (
p
= 0.01), respectively. No other expression changes related to stress or apoptotic genes were observed. Extended clinical follow-up involving ten family members showed that two healthy individuals carried the same mutation with no sign of diabetes in the clinical screen except for a slight increase in IA-2 antibody in one of them, suggesting incomplete penetrance. In conclusion, we describe
EDEM2
as a likely/potential novel diabetes gene, in which inhibition in vitro reduces the expression of β-cell genes involved in the glucose‐stimulated insulin secretion (GSIS) pathway, leading to an overall suppression of insulin secretion but not apoptosis.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><doi>10.1007/s00438-020-01695-5</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-0569-2988</orcidid></addata></record> |
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| language | eng |
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| source | Springer Nature |
| subjects | Animal Genetics and Genomics Apoptosis Autoantibodies Beta cells Biochemistry Biomedical and Life Sciences Childhood Children Diabetes Diabetes mellitus Genes Glucose transporter Human Genetics Insulin Insulin secretion Life Sciences Microbial Genetics and Genomics mRNA Mutation Original Article Pancreas Plant Genetics and Genomics Secretion |
| title | A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion |
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