Monica M Franca1, Xingfa Han2,3, Mariana F A Funari1, Antonio M Lerario4, Mirian Y Nishi1,5, Eveline G P Fontenele6, Sorahia Domenice1, Alexander A L Jorge7, David Garcia-Galiano2, Carol F Elias2,8, Berenice B Mendonca1,5. 1. Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil. 2. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. 3. Isotope Research Laboratory, Sichuan Agricultural University, Ya'an, China. 4. Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan. 5. Laboratorio de Sequenciamento em Larga Escala, Faculdade de Medicina Universidade de São Paulo, São Paulo, SP, Brazil. 6. Serviço de Endocrinologia e Diabetes do Hospital Universitario Walter Cantidio, Universidade Federal do Ceara, Fortaleza, CE, Brazil. 7. Unidade de Endocrinologia Genetica/LIM25, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil. 8. Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.
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.Asp50Gly) 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 (Polr3hD50G) were viable but showed delayed pubertal development, characterized by late first estrus or preputial separation. The Polr3hD50G 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. Polr3hD50G 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.
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.Asp50Gly) 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 (Polr3hD50G) were viable but showed delayed pubertal development, characterized by late first estrus or preputial separation. The Polr3hD50G 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. Polr3hD50G 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 humaninfertility. Screening of the POLR3H gene may elucidate POI cases without previously identified genetic causes, supporting approaches of genetic counseling.
Authors: Kui Liu; Singareddy Rajareddy; Lian Liu; Krishna Jagarlamudi; Karin Boman; Gunnar Selstam; Pradeep Reddy Journal: Dev Biol Date: 2006-08-05 Impact factor: 3.582
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