| Full text | |
| Author(s): Show less - |
Franca, Monica M.
[1]
;
Han, Xingfa
[2, 3]
;
Funari, Mariana F. A.
[1]
;
Lerario, Antonio M.
[4]
;
Nishi, Mirian Y.
[1, 5]
;
Fontenele, Eveline G. P.
[6]
;
Domenice, Sorahia
[1]
;
Jorge, Alexander A. L.
[7]
;
Garcia-Galiano, David
[2]
;
Elias, Carol F.
[2, 8]
;
Mendonca, Berenice B.
[1, 5]
Total Authors: 11
|
| Affiliation: | [1] Univ Sao Paulo, Unidade Endocrinol Desenvolvimento, Lab Hormonios & Genet Mol LIM42, Hosp Clin, Fac Med, BR-05403900 Sao Paulo, SP - Brazil
[2] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 - USA
[3] Sichuan Agr Univ, Isotope Res Lab, Yaan 625014 - Peoples R China
[4] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA
[5] Univ Sao Paulo, Lab Sequenciamento Larga Escala, Fac Med, BR-01246903 Sao Paulo, SP - Brazil
[6] Univ Fed Ceara, Serv Endocrinol & Diabet, Hosp Univ Walter Cantidio, BR-60430370 Fortaleza, CE - Brazil
[7] Univ Sao Paulo, Fac Med, Unidade Endocrinol Genet LIM25, BR-01246903 Sao Paulo, SP - Brazil
[8] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 - USA
Total Affiliations: 8
|
| Document type: | Journal article |
| Source: | JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 104, n. 7, p. 2827-2841, JUL 2019. |
| Web of Science Citations: | 2 |
| Abstract | |
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. (AU) | |
| FAPESP's process: | 13/02162-8 - Molecular pathogenesis and characterization of monogenic developmental diseases: a route to translational medicine |
| Grantee: | Berenice Bilharinho de Mendonça |
| Support Opportunities: | Research Projects - Thematic Grants |