Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism
Wieland I, Schanze I, Felgendreher IM, Barthlen W, Vogelgesang S, Mohnike K, Zenker M (2022)
Frontiers in Endocrinology 13: 1015244.
Zeitschriftenaufsatz
| Veröffentlicht | Englisch
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Autor*in
Wieland, Ilse;
Schanze, Ina;
Felgendreher, Ina Marianti;
Barthlen, WinfriedUniBi;
Vogelgesang, Silke;
Mohnike, Klaus;
Zenker, Martin
Abstract / Bemerkung
Background:
The focal form of CHI is caused by an autosomal recessive pathogenic variant affecting the paternal homologue of genes ABCC8 or KCNJ11 and a second somatic event specifically occurring in the affected islet of Langerhans. The approach of this study was to integrate the genetic changes occurring in pancreatic focal lesions of CHI at the genomic and transcriptional level.
Research Design and Methods:
Patients receiving therapeutic surgery and with proven ABCC8 or KCNJ11 pathogenic variants were selected and analyzed for loss of heterozygosity (LOH), changes in copy number and uniparental disomy (UPD) on the short am of chromosome 11 by molecular microarray analysis and methylation-specific MLPA. Gene expression was analyzed by RT-PCR and Massive Analysis of cDNA Ends (MACE).
Results:
Both genes, ABCC8 and KCNJ11, are located in proximity to the Beckwith-Wiedemann (BWS) imprinting control region on chromosome 11p15. Somatic paternal uniparental isodisomy (UPD) at chromosome 11p was identified as second genetic event in focal lesions resulting in LOH and monoallelic expression of the mutated ABCC8/KCNJ11 alleles. Of five patients with samples available for microarray analysis, the breakpoints of UPD on chromosome 11p were different. Samples of two patients were analyzed further for changes in gene expression. Profound downregulation of growth suppressing genes CDKN1 and H19 was detected in focal lesions whereas growth promoting gene ASCL2 and pancreatic transcription factors of the endocrine cell lineage were upregulated.
Conclusions:
Paternal UPD on the short arm of chromosome 11 appears to be the major second genetic event specifically within focal lesions of CHI but no common breakpoint for UDP can be delineated. We show for the first time upregulation of growth promoting ASCL2 (achaete-scute homolog 2) suggestive of a driving factor in postnatal focal expansion in addition to downregulation of growth suppressing genes CDKN1C and H19.
The focal form of CHI is caused by an autosomal recessive pathogenic variant affecting the paternal homologue of genes ABCC8 or KCNJ11 and a second somatic event specifically occurring in the affected islet of Langerhans. The approach of this study was to integrate the genetic changes occurring in pancreatic focal lesions of CHI at the genomic and transcriptional level.
Research Design and Methods:
Patients receiving therapeutic surgery and with proven ABCC8 or KCNJ11 pathogenic variants were selected and analyzed for loss of heterozygosity (LOH), changes in copy number and uniparental disomy (UPD) on the short am of chromosome 11 by molecular microarray analysis and methylation-specific MLPA. Gene expression was analyzed by RT-PCR and Massive Analysis of cDNA Ends (MACE).
Results:
Both genes, ABCC8 and KCNJ11, are located in proximity to the Beckwith-Wiedemann (BWS) imprinting control region on chromosome 11p15. Somatic paternal uniparental isodisomy (UPD) at chromosome 11p was identified as second genetic event in focal lesions resulting in LOH and monoallelic expression of the mutated ABCC8/KCNJ11 alleles. Of five patients with samples available for microarray analysis, the breakpoints of UPD on chromosome 11p were different. Samples of two patients were analyzed further for changes in gene expression. Profound downregulation of growth suppressing genes CDKN1 and H19 was detected in focal lesions whereas growth promoting gene ASCL2 and pancreatic transcription factors of the endocrine cell lineage were upregulated.
Conclusions:
Paternal UPD on the short arm of chromosome 11 appears to be the major second genetic event specifically within focal lesions of CHI but no common breakpoint for UDP can be delineated. We show for the first time upregulation of growth promoting ASCL2 (achaete-scute homolog 2) suggestive of a driving factor in postnatal focal expansion in addition to downregulation of growth suppressing genes CDKN1C and H19.
Stichworte
ABCC8;
Achaete-scute complex homolog 2;
CHI;
KCNJ11;
UPD 11p
Erscheinungsjahr
2022
Zeitschriftentitel
Frontiers in Endocrinology
Band
13
Art.-Nr.
1015244
Urheberrecht / Lizenzen
eISSN
1664-2392
Page URI
https://pub.uni-bielefeld.de/record/2967108
Zitieren
Wieland I, Schanze I, Felgendreher IM, et al. Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism. Frontiers in Endocrinology. 2022;13: 1015244.
Wieland, I., Schanze, I., Felgendreher, I. M., Barthlen, W., Vogelgesang, S., Mohnike, K., & Zenker, M. (2022). Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism. Frontiers in Endocrinology, 13, 1015244. https://doi.org/10.3389/fendo.2022.1015244
Wieland, Ilse, Schanze, Ina, Felgendreher, Ina Marianti, Barthlen, Winfried, Vogelgesang, Silke, Mohnike, Klaus, and Zenker, Martin. 2022. “Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism”. Frontiers in Endocrinology 13: 1015244.
Wieland, I., Schanze, I., Felgendreher, I. M., Barthlen, W., Vogelgesang, S., Mohnike, K., and Zenker, M. (2022). Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism. Frontiers in Endocrinology 13:1015244.
Wieland, I., et al., 2022. Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism. Frontiers in Endocrinology, 13: 1015244.
I. Wieland, et al., “Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism”, Frontiers in Endocrinology, vol. 13, 2022, : 1015244.
Wieland, I., Schanze, I., Felgendreher, I.M., Barthlen, W., Vogelgesang, S., Mohnike, K., Zenker, M.: Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism. Frontiers in Endocrinology. 13, : 1015244 (2022).
Wieland, Ilse, Schanze, Ina, Felgendreher, Ina Marianti, Barthlen, Winfried, Vogelgesang, Silke, Mohnike, Klaus, and Zenker, Martin. “Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism”. Frontiers in Endocrinology 13 (2022): 1015244.
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