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Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity
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| Zeitschriftentitel: | The Journal of Clinical Endocrinology & Metabolism |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , , , , , , , , , |
| In: | The Journal of Clinical Endocrinology & Metabolism, 89, 2004, 12, S. 6224-6234 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
The Endocrine Society
|
| Schlagwörter: |
| author_facet |
Tornovsky, Sharona Crane, Ana Cosgrove, Karen E. Hussain, Khalid Lavie, Judith Heyman, Ma’ayan Nesher, Yaron Kuchinski, Na’ama Ben-Shushan, Etti Shatz, Olga Nahari, Efrat Potikha, Tamara Zangen, David Tenenbaum-Rakover, Yardena de Vries, Liat Argente, Jesús Gracia, Ricardo Landau, Heddy Eliakim, Alon Lindley, Keith Dunne, Mark J. Aguilar-Bryan, Lydia Glaser, Benjamin Tornovsky, Sharona Crane, Ana Cosgrove, Karen E. Hussain, Khalid Lavie, Judith Heyman, Ma’ayan Nesher, Yaron Kuchinski, Na’ama Ben-Shushan, Etti Shatz, Olga Nahari, Efrat Potikha, Tamara Zangen, David Tenenbaum-Rakover, Yardena de Vries, Liat Argente, Jesús Gracia, Ricardo Landau, Heddy Eliakim, Alon Lindley, Keith Dunne, Mark J. Aguilar-Bryan, Lydia Glaser, Benjamin |
|---|---|
| author |
Tornovsky, Sharona Crane, Ana Cosgrove, Karen E. Hussain, Khalid Lavie, Judith Heyman, Ma’ayan Nesher, Yaron Kuchinski, Na’ama Ben-Shushan, Etti Shatz, Olga Nahari, Efrat Potikha, Tamara Zangen, David Tenenbaum-Rakover, Yardena de Vries, Liat Argente, Jesús Gracia, Ricardo Landau, Heddy Eliakim, Alon Lindley, Keith Dunne, Mark J. Aguilar-Bryan, Lydia Glaser, Benjamin |
| spellingShingle |
Tornovsky, Sharona Crane, Ana Cosgrove, Karen E. Hussain, Khalid Lavie, Judith Heyman, Ma’ayan Nesher, Yaron Kuchinski, Na’ama Ben-Shushan, Etti Shatz, Olga Nahari, Efrat Potikha, Tamara Zangen, David Tenenbaum-Rakover, Yardena de Vries, Liat Argente, Jesús Gracia, Ricardo Landau, Heddy Eliakim, Alon Lindley, Keith Dunne, Mark J. Aguilar-Bryan, Lydia Glaser, Benjamin The Journal of Clinical Endocrinology & Metabolism Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity Biochemistry (medical) Clinical Biochemistry Endocrinology Biochemistry Endocrinology, Diabetes and Metabolism |
| author_sort |
tornovsky, sharona |
| spelling |
Tornovsky, Sharona Crane, Ana Cosgrove, Karen E. Hussain, Khalid Lavie, Judith Heyman, Ma’ayan Nesher, Yaron Kuchinski, Na’ama Ben-Shushan, Etti Shatz, Olga Nahari, Efrat Potikha, Tamara Zangen, David Tenenbaum-Rakover, Yardena de Vries, Liat Argente, Jesús Gracia, Ricardo Landau, Heddy Eliakim, Alon Lindley, Keith Dunne, Mark J. Aguilar-Bryan, Lydia Glaser, Benjamin 0021-972X 1945-7197 The Endocrine Society Biochemistry (medical) Clinical Biochemistry Endocrinology Biochemistry Endocrinology, Diabetes and Metabolism http://dx.doi.org/10.1210/jc.2004-1233 <jats:title>Abstract</jats:title> <jats:p>Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (KIR6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on β-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.</jats:p> Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity The Journal of Clinical Endocrinology & Metabolism |
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The Endocrine Society, 2004 |
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| title |
Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_unstemmed |
Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_full |
Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_fullStr |
Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_full_unstemmed |
Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_short |
Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_sort |
hyperinsulinism of infancy: novel abcc8 and kcnj11 mutations and evidence for additional locus heterogeneity |
| topic |
Biochemistry (medical) Clinical Biochemistry Endocrinology Biochemistry Endocrinology, Diabetes and Metabolism |
| url |
http://dx.doi.org/10.1210/jc.2004-1233 |
| publishDate |
2004 |
| physical |
6224-6234 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (KIR6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on β-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.</jats:p> |
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| author | Tornovsky, Sharona, Crane, Ana, Cosgrove, Karen E., Hussain, Khalid, Lavie, Judith, Heyman, Ma’ayan, Nesher, Yaron, Kuchinski, Na’ama, Ben-Shushan, Etti, Shatz, Olga, Nahari, Efrat, Potikha, Tamara, Zangen, David, Tenenbaum-Rakover, Yardena, de Vries, Liat, Argente, Jesús, Gracia, Ricardo, Landau, Heddy, Eliakim, Alon, Lindley, Keith, Dunne, Mark J., Aguilar-Bryan, Lydia, Glaser, Benjamin |
| author_facet | Tornovsky, Sharona, Crane, Ana, Cosgrove, Karen E., Hussain, Khalid, Lavie, Judith, Heyman, Ma’ayan, Nesher, Yaron, Kuchinski, Na’ama, Ben-Shushan, Etti, Shatz, Olga, Nahari, Efrat, Potikha, Tamara, Zangen, David, Tenenbaum-Rakover, Yardena, de Vries, Liat, Argente, Jesús, Gracia, Ricardo, Landau, Heddy, Eliakim, Alon, Lindley, Keith, Dunne, Mark J., Aguilar-Bryan, Lydia, Glaser, Benjamin, Tornovsky, Sharona, Crane, Ana, Cosgrove, Karen E., Hussain, Khalid, Lavie, Judith, Heyman, Ma’ayan, Nesher, Yaron, Kuchinski, Na’ama, Ben-Shushan, Etti, Shatz, Olga, Nahari, Efrat, Potikha, Tamara, Zangen, David, Tenenbaum-Rakover, Yardena, de Vries, Liat, Argente, Jesús, Gracia, Ricardo, Landau, Heddy, Eliakim, Alon, Lindley, Keith, Dunne, Mark J., Aguilar-Bryan, Lydia, Glaser, Benjamin |
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| description | <jats:title>Abstract</jats:title> <jats:p>Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (KIR6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on β-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.</jats:p> |
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| institution | DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161 |
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| spelling | Tornovsky, Sharona Crane, Ana Cosgrove, Karen E. Hussain, Khalid Lavie, Judith Heyman, Ma’ayan Nesher, Yaron Kuchinski, Na’ama Ben-Shushan, Etti Shatz, Olga Nahari, Efrat Potikha, Tamara Zangen, David Tenenbaum-Rakover, Yardena de Vries, Liat Argente, Jesús Gracia, Ricardo Landau, Heddy Eliakim, Alon Lindley, Keith Dunne, Mark J. Aguilar-Bryan, Lydia Glaser, Benjamin 0021-972X 1945-7197 The Endocrine Society Biochemistry (medical) Clinical Biochemistry Endocrinology Biochemistry Endocrinology, Diabetes and Metabolism http://dx.doi.org/10.1210/jc.2004-1233 <jats:title>Abstract</jats:title> <jats:p>Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (KIR6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on β-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.</jats:p> Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity The Journal of Clinical Endocrinology & Metabolism |
| spellingShingle | Tornovsky, Sharona, Crane, Ana, Cosgrove, Karen E., Hussain, Khalid, Lavie, Judith, Heyman, Ma’ayan, Nesher, Yaron, Kuchinski, Na’ama, Ben-Shushan, Etti, Shatz, Olga, Nahari, Efrat, Potikha, Tamara, Zangen, David, Tenenbaum-Rakover, Yardena, de Vries, Liat, Argente, Jesús, Gracia, Ricardo, Landau, Heddy, Eliakim, Alon, Lindley, Keith, Dunne, Mark J., Aguilar-Bryan, Lydia, Glaser, Benjamin, The Journal of Clinical Endocrinology & Metabolism, Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity, Biochemistry (medical), Clinical Biochemistry, Endocrinology, Biochemistry, Endocrinology, Diabetes and Metabolism |
| title | Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_full | Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_fullStr | Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_full_unstemmed | Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_short | Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| title_sort | hyperinsulinism of infancy: novel abcc8 and kcnj11 mutations and evidence for additional locus heterogeneity |
| title_unstemmed | Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity |
| topic | Biochemistry (medical), Clinical Biochemistry, Endocrinology, Biochemistry, Endocrinology, Diabetes and Metabolism |
| url | http://dx.doi.org/10.1210/jc.2004-1233 |