Exome Sequencing Reveals the POLR3H Gene as a Novel Cause of Primary Ovarian Insufficiency

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art_FRANCA_Exome_Sequencing_Reveals_the_POLR3H_Gene_as_a_2019.PDF (2.46 MB)
Citações na Scopus
25
Tipo de produção
article
Data de publicação
2019
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
ENDOCRINE SOC
Autores
HAN, Xingfa
LERARIO, Antonio M.
FONTENELE, Eveline G. P.
GARCIA-GALIANO, David
ELIAS, Carol F.
Citação
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v.104, n.7, p.2827-2841, 2019
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Context: Primary ovarian insufficiency (POI) is a cause of female infertility. However, the genetic etiology of this disorder remains unknown in most patients with POI. Objective: To investigate the genetic etiology of idiopathic POI. Patients and Methods: We performed whole-exome sequencing of 11 families with idiopathic POI. To gain insights into the potential mechanisms associated with this mutation, we generated two mouse lines via clustered regularly interspaced short palindromic repeats/Cas9 technology. Results: A pathogenic homozygous missense mutation (c.149A>G; p.Asp50G ly) in the POLR3H gene in two unrelated families was identified. Pathogenic mutations in this subunit have not been associated with human disorders. Loss-of-function Polr3h mutation in mice caused early embryonic lethality. Mice with homozygous point mutation (Polr3h(D50G)) were viable but showed delayed pubertal development, characterized by late first estrus or preputial separation. The Polr3h(D50G) female and male mice showed decreased fertility later in life, associated with small litter size and increased time to pregnancy or to impregnate a female. Polr3h(D50G) mice displayed decreased expression of ovarian Foxo3a and lower numbers of primary follicles. Conclusion: Our manuscript provides a case of POI caused by missense mutation in POLR3H, expanding the knowledge of molecular pathways of the ovarian function and human infertility. Screening of the POLR3H gene may elucidate POI cases without previously identified genetic causes, supporting approaches of genetic counseling.
Palavras-chave
URI
https://observatorio.fm.usp.br/handle/OPI/32984
Referências
  1. Alvarez-Castro JM, 2011, GENETICA, V139, P1119, DOI 10.1007/s10709-011-9614-9
  2. Becker K, 2011, ADV PROTOCOLS ANIMAL, P99
  3. Bernard G, 2011, AM J HUM GENET, V89, P415, DOI 10.1016/j.ajhg.2011.07.014
  4. Castrillon DH, 2003, SCIENCE, V301, P215, DOI 10.1126/science.1086336
  5. Cheng Y, 2013, FASEB J, V27, P2175, DOI 10.1096/fj.12-223412
  6. Choquet K, 2017, MOL BRAIN, V10, DOI 10.1186/s13041-017-0294-y
  7. Cong L, 2013, SCIENCE, V339, P819, DOI 10.1126/science.1231143
  8. Craig J, 2007, FRONT BIOSCI-LANDMRK, V12, P3628, DOI 10.2741/2338
  9. Donato J, 2013, NEUROSCIENCE, V241, P67, DOI 10.1016/j.neuroscience.2013.03.013
  10. Drummond AE, 2006, REPROD BIOL ENDOCRIN, V4, DOI 10.1186/1477-7827-4-16
  11. Dumay-Odelot H, 2010, CELL CYCLE, V9, P3687, DOI 10.4161/cc.9.18.13203
  12. Franca MM, 2017, ENDOCRINE, V58, P442, DOI 10.1007/s12020-017-1459-2
  13. Franca MM, 2017, SEX DEV, V11, P137, DOI 10.1159/000477193
  14. Garrison A, 2012, HAPLOTYPE BASED VARI
  15. Haeussler M, 2016, GENOME BIOL, V17, DOI 10.1186/s13059-016-1012-2
  16. Huhtaniemi I, 2018, TRENDS ENDOCRIN MET, V29, P400, DOI 10.1016/j.tem.2018.03.010
  17. Laissue P, 2018, MOL CELL ENDOCRINOL, V460, P170, DOI 10.1016/j.mce.2017.07.021
  18. Li H, 2010, BIOINFORMATICS, V26, P589, DOI 10.1093/bioinformatics/btp698
  19. Liu K, 2006, DEV BIOL, V299, P1, DOI 10.1016/j.ydbio.2006.07.038
  20. Liu L, 2007, DEVELOPMENT, V134, P199, DOI 10.1242/dev.02667
  21. Mali P, 2013, SCIENCE, V339, P823, DOI 10.1126/science.1232033
  22. Mashiko D, 2013, SCI REP-UK, V3, DOI 10.1038/srep03355
  23. Matzuk MM, 2008, NAT MED, V14, P1197, DOI 10.1038/nm.f.1895
  24. MENDONCA BB, 1994, J MOL ENDOCRINOL, V12, P119, DOI 10.1677/jme.0.0120119
  25. Naslavsky MS, 2017, HUM MUTAT, V38, P751, DOI 10.1002/humu.23220
  26. Nguyen D, 2008, DIS MODEL MECH, V1, P56, DOI 10.1242/dmm.000232
  27. Paquet D, 2016, NATURE, V533, P125, DOI 10.1038/nature17664
  28. Ran FA, 2013, NAT PROTOC, V8, P2281, DOI 10.1038/nprot.2013.143
  29. Richards MR, 2017, J MED GENET, V54, P19, DOI 10.1136/jmedgenet-2016-104064
  30. Richards S, 2015, GENET MED, V17, P405, DOI 10.1038/gim.2015.30
  31. Ricken A, 2002, ENDOCRINOLOGY, V143, P2741, DOI 10.1210/en.143.7.2741
  32. Roy A, 2010, NAT PROTOC, V5, P725, DOI 10.1038/nprot.2010.5
  33. Saitsu H, 2011, AM J HUM GENET, V89, P644, DOI 10.1016/j.ajhg.2011.10.003
  34. Sakurai T, 2014, BMC BIOTECHNOL, V14, DOI 10.1186/1472-6750-14-69
  35. Scott MM, 2009, J COMP NEUROL, V514, P518, DOI 10.1002/cne.22025
  36. Tetreault M, 2011, AM J HUM GENET, V89, P652, DOI 10.1016/j.ajhg.2011.10.006
  37. Tucker EJ, 2016, ENDOCR REV, V37, P609, DOI 10.1210/er.2016-1047
  38. Van Keuren ML, 2009, TRANSGENIC RES, V18, P769, DOI 10.1007/s11248-009-9271-2
  39. Wang K, 2010, NUCLEIC ACIDS RES, V38, DOI 10.1093/nar/gkq603
  40. Webber L, 2016, HUM REPROD, V31, P926, DOI 10.1093/humrep/dew027
  41. White RJ, 2005, NAT REV MOL CELL BIO, V6, P69, DOI 10.1038/nrm1551
  42. Yang JY, 2015, NAT METHODS, V12, P7, DOI 10.1038/nmeth.3213
  43. Zhang Y, 2008, BMC BIOINFORMATICS, V9, DOI 10.1186/1471-2105-9-40
  44. Zigman JM, 2006, J COMP NEUROL, V494, P528, DOI 10.1002/cne.20823

Coleções
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/25
Artigos e Materiais de Revistas Científicas - LIM/42