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Pregled bibliografske jedinice broj: 1260819

Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism

(International Congenital Hyperinsulinism Consortium) Wakeling, Matthew N.; Owens, Nick D. L.; Hopkinson, Jessica R.; Johnson, Matthew B.; Houghton, Jayne A. L.; Dastamani, Antonia; Flaxman, Christine S.; Wyatt, Rebecca C.; Hewat, Thomas I.; Hopkins, Jasmin J. et al.
Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism // Nature genetics, 54 (2022), 11; 1615-1620 doi:10.1038/s41588-022-01204-x (međunarodna recenzija, članak, znanstveni)

CROSBI ID: 1260819 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism

Autori
Wakeling, Matthew N. ; Owens, Nick D. L. ; Hopkinson, Jessica R. ; Johnson, Matthew B. ; Houghton, Jayne A. L. ; Dastamani, Antonia ; Flaxman, Christine S. ; Wyatt, Rebecca C. ; Hewat, Thomas I. ; Hopkins, Jasmin J. ; Laver, Thomas W. ; van Heugten, Rachel ; Weedon, Michael N. ; De Franco, Elisa ; Patel, Kashyap A. ; Ellard, Sian ; Morgan, Noel G. ; Cheesman, Edmund ; Banerjee, Indraneel ; Hattersley, Andrew T. ; Dunne, Mark J. ; Richardson, Sarah J. ; Flanagan, Sarah E.

Kolaboracija
International Congenital Hyperinsulinism Consortium

Izvornik
Nature genetics (1061-4036) 54 (2022), 11; 1615-1620

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
congenital hyperinsulinism ; HK1 gene

Sažetak
Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function. This silencing is largely controlled by non-coding elements, and their disruption might cause human disease. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1). HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a 'disallowed gene' in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti



POVEZANOST RADA

Ustanove:
Medicinski fakultet, Zagreb,
Klinički bolnički centar Zagreb

Profili:

Avatar Url Ivo Barić (autor)

Poveznice na cjeloviti tekst rada:

doi

Citiraj ovu publikaciju:

(International Congenital Hyperinsulinism Consortium) Wakeling, Matthew N.; Owens, Nick D. L.; Hopkinson, Jessica R.; Johnson, Matthew B.; Houghton, Jayne A. L.; Dastamani, Antonia; Flaxman, Christine S.; Wyatt, Rebecca C.; Hewat, Thomas I.; Hopkins, Jasmin J. et al.
Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism // Nature genetics, 54 (2022), 11; 1615-1620 doi:10.1038/s41588-022-01204-x (međunarodna recenzija, članak, znanstveni)
(International Congenital Hyperinsulinism Consortium) (International Congenital Hyperinsulinism Consortium) Wakeling, M., Owens, N., Hopkinson, J., Johnson, M., Houghton, J., Dastamani, A., Flaxman, C., Wyatt, R., Hewat, T. & Hopkins, J. (2022) Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism. Nature genetics, 54 (11), 1615-1620 doi:10.1038/s41588-022-01204-x.
@article{article, author = {Wakeling, Matthew N. and Owens, Nick D. L. and Hopkinson, Jessica R. and Johnson, Matthew B. and Houghton, Jayne A. L. and Dastamani, Antonia and Flaxman, Christine S. and Wyatt, Rebecca C. and Hewat, Thomas I. and Hopkins, Jasmin J. and Laver, Thomas W. and van Heugten, Rachel and Weedon, Michael N. and De Franco, Elisa and Patel, Kashyap A. and Ellard, Sian and Morgan, Noel G. and Cheesman, Edmund and Banerjee, Indraneel and Hattersley, Andrew T. and Dunne, Mark J. and Richardson, Sarah J. and Flanagan, Sarah E.}, year = {2022}, pages = {1615-1620}, DOI = {10.1038/s41588-022-01204-x}, keywords = {congenital hyperinsulinism, HK1 gene}, journal = {Nature genetics}, doi = {10.1038/s41588-022-01204-x}, volume = {54}, number = {11}, issn = {1061-4036}, title = {Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism}, keyword = {congenital hyperinsulinism, HK1 gene} }
@article{article, author = {Wakeling, Matthew N. and Owens, Nick D. L. and Hopkinson, Jessica R. and Johnson, Matthew B. and Houghton, Jayne A. L. and Dastamani, Antonia and Flaxman, Christine S. and Wyatt, Rebecca C. and Hewat, Thomas I. and Hopkins, Jasmin J. and Laver, Thomas W. and van Heugten, Rachel and Weedon, Michael N. and De Franco, Elisa and Patel, Kashyap A. and Ellard, Sian and Morgan, Noel G. and Cheesman, Edmund and Banerjee, Indraneel and Hattersley, Andrew T. and Dunne, Mark J. and Richardson, Sarah J. and Flanagan, Sarah E.}, year = {2022}, pages = {1615-1620}, DOI = {10.1038/s41588-022-01204-x}, keywords = {congenital hyperinsulinism, HK1 gene}, journal = {Nature genetics}, doi = {10.1038/s41588-022-01204-x}, volume = {54}, number = {11}, issn = {1061-4036}, title = {Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism}, keyword = {congenital hyperinsulinism, HK1 gene} }

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE
  • Nature Index

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