<i>POLR1A</i> variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies

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Citações na Scopus
4
Tipo de produção
article
Data de publicação
2023
DOI
Scopus
Web of Science
PubMed
Dimensions
Título da Revista
ISSN da Revista
Título do Volume
Editora
CELL PRESS
Autores
SMALLWOOD, Kelly
WATT, Kristin E. N.
IDE, Satoru
BALTRUNAITE, Kristina
BRUNSWICK, Chad
INSKEEP, Katherine
CAPANNARI, Corrine
ADAM, Margaret P.
BEGTRUP, Amber
Citação
AMERICAN JOURNAL OF HUMAN GENETICS, v.110, n.5, p.809-825, 2023
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of indi-vidual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to reca-pitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.
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URI
https://observatorio.fm.usp.br/handle/OPI/59218
Referências
  1. [Anonymous], 1989, CLADISTICS, DOI 10.1111/J.1096-0031.1989.TB00562.X
  2. Ariani F, 2008, AM J HUM GENET, V83, P89, DOI 10.1016/j.ajhg.2008.05.015
  3. Chau KF, 2018, ELIFE, V7, DOI 10.7554/eLife.36998
  4. Conway SJ, 2003, GENESIS, V35, P1, DOI 10.1002/gene.10152
  5. da Rocha LA, 2021, CLIN GENET, V100, P615, DOI 10.1111/cge.14041
  6. Danielian PS, 1998, CURR BIOL, V8, P1323, DOI 10.1016/S0960-9822(07)00562-3
  7. Dauwerse JG, 2011, NAT GENET, V43, P20, DOI 10.1038/ng.724
  8. EDMONDSON DG, 1994, DEVELOPMENT, V120, P1251
  9. Edvardson S, 2017, AM J HUM GENET, V101, P267, DOI 10.1016/j.ajhg.2017.07.002
  10. Falcon KT, 2022, P NATL ACAD SCI USA, V119, DOI 10.1073/pnas.2116974119
  11. Gandhi S, 2018, INT J DEV BIOL, V62, P183, DOI 10.1387/ijdb.180038sg
  12. Gauquelin L, 2019, NEUROL-GENET, V5, DOI 10.1212/NXG.0000000000000369
  13. Gazda H.T., 2008, AM J HUM GENET
  14. Gripp K.W., 2014, AM I MED GENET A
  15. Haeussler M, 2016, GENOME BIOL, V17, DOI 10.1186/s13059-016-1012-2
  16. Ide S, 2022, BIOESSAYS, V44, DOI 10.1002/bies.202200043
  17. Ide S, 2020, SCI ADV, V6, DOI 10.1126/sciadv.abb5953
  18. Kara B, 2017, EUR J HUM GENET, V25, P315, DOI 10.1038/ejhg.2016.183
  19. Karczewski KJ, 2020, NATURE, V581, P434, DOI 10.1038/s41586-020-2308-7
  20. Kawaguchi D, 2016, DEV BIOL, V412, P139, DOI 10.1016/j.ydbio.2016.02.011
  21. Kimberly E., 2010, HEART DEV REGENERATI, P417
  22. Laferté A, 2006, GENE DEV, V20, P2030, DOI 10.1101/gad.386106
  23. Landowski M., 2013, Hum Genet
  24. Matsumori H, 2022, LIFE SCI ALLIANCE, V5, DOI 10.26508/lsa.202101045
  25. Matsuoka T, 2005, NATURE, V436, P347, DOI 10.1038/nature03837
  26. Misiaszek AD, 2021, NAT STRUCT MOL BIOL, V28, P997, DOI 10.1038/s41594-021-00693-4
  27. Muzumdar MD, 2007, GENESIS, V45, P593, DOI 10.1002/dvg.20335
  28. Pradat P, 2003, PEDIATR CARDIOL, V24, P195, DOI 10.1007/s00246-002-9401-6
  29. Richards S, 2015, GENET MED, V17, P405, DOI 10.1038/gim.2015.30
  30. Sanchez E, 2020, GENET MED, V22, P547, DOI 10.1038/s41436-019-0669-9
  31. Schaefer E, 2014, GENET MED, V16, P720, DOI 10.1038/gim.2014.12
  32. Schindelin J, 2012, NAT METHODS, V9, P676, DOI [10.1038/NMETH.2019, 10.1038/nmeth.2019]
  33. Scott MA, 2019, METHODS MOL BIOL, V1874, P169, DOI 10.1007/978-1-4939-8831-0_9
  34. Shamir L, 2008, SOURCE CODE BIOL MED, V3, DOI 10.1186/1751-0473-3-13
  35. Shenoy RD, 2022, CLEFT PALATE-CRAN J, V59, P1346, DOI 10.1177/10556656211050006
  36. Skarnes WC, 2011, NATURE, V474, P337, DOI 10.1038/nature10163
  37. Sobreira Nara, 2015, Hum Mutat, V36, P928, DOI 10.1002/humu.22844
  38. Stottmann RW, 2004, DEVELOPMENT, V131, P2205, DOI 10.1242/dev.01086
  39. Takase Y, 2013, DEV GROWTH DIFFER, V55, P792, DOI 10.1111/dgd.12106
  40. Thiffault I, 2015, NAT COMMUN, V6, DOI 10.1038/ncomms8623
  41. Verzi MP, 2005, DEV BIOL, V287, P134, DOI 10.1016/j.ydbio.2005.08.041
  42. Vincent M, 2016, GENET MED, V18, P49, DOI 10.1038/gim.2015.29
  43. Waldo KL, 2005, DEV BIOL, V281, P78, DOI 10.1016/j.ydbio.2005.02.012
  44. Watt KEN, 2018, HUM MOL GENET, V27, P2628, DOI 10.1093/hmg/ddy172
  45. Watt KristinE., 2014, Neural Crest Cells, P361, DOI [DOI 10.1016/B978-0-12-401730-6.00018-1, 10.1016/B978-0-12-401730-6.00018-1]
  46. Weaver KN, 2015, AM J HUM GENET, V96, P765, DOI 10.1016/j.ajhg.2015.03.011
  47. Willig TN, 1999, PEDIATR RES, V46, P553, DOI 10.1203/00006450-199911000-00011
  48. Yelbuz TM, 2002, CIRCULATION, V106, P504, DOI 10.1161/01.CIR.0000023044.44974.8A
  49. Yuan CL, 2017, ADV EXP MED BIOL, V1016, P75, DOI 10.1007/978-3-319-63904-8_4

Coleções
Artigos e Materiais de Revistas Científicas - HC/ICr