Research ArticleDevelopmentReproductive biology Open Access | 10.1172/JCI161701

Adriana Lofrano-Porto,1,2,3 Sidney Alcântara Pereira,1,3 Andrew Dauber,4,5 Jordana C.B. Bloom,6 Audrey N. Fontes,3 Naomi Asimow,3 Olívia Laquis de Moraes,1 Petra Ariadne T. Araujo,1 Ana Paula Abreu,3 Michael H. Guo,7,8,9 Silviene F. De Oliveira,10,11 Han Liu,12 Charles Lee,11 Wendy Kuohung,13 Michella S. Coelho,1 Rona S. Carroll,3 Rulang Jiang,12,14 and Ursula B. Kaiser3

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Lofrano-Porto, A. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Pereira, S. in: JCI | PubMed | Google Scholar |

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Dauber, A. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Bloom, J. in: JCI | PubMed | Google Scholar |

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Fontes, A. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Asimow, N. in: JCI | PubMed | Google Scholar |

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by de Moraes, O. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Araujo, P. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Abreu, A. in: JCI | PubMed | Google Scholar |

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Guo, M. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by De Oliveira, S. in: JCI | PubMed | Google Scholar |

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Liu, H. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Lee, C. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Kuohung, W. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Coelho, M. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Carroll, R. in: JCI | PubMed | Google Scholar

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

Find articles by Jiang, R. in: JCI | PubMed | Google Scholar |

1Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.

2Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.

3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

4Division of Endocrinology, Children’s National Hospital, Washington, DC, USA.

5Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA.

6Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.

8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

9Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

10Department of Genetics and Morphology, Institute of Biology, University of Brasilia, Brasilia-DF, Brazil.

11Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

12Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

13Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

14Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Address correspondence to: Ursula B. Kaiser, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston Massachusetts 02115, USA. Phone: 1.617.525.8867; Email: ukaiser@bwh.harvard.edu.

Authorship note: ALP and SAP contributed equally to this work.

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Authorship note: ALP and SAP contributed equally to this work.

Published October 17, 2023 - More info

Published in Volume 133, Issue 23 on December 1, 2023
J Clin Invest. 2023;133(23):e161701. https://doi.org/10.1172/JCI161701.
© 2023 Lofrano-Porto et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published October 17, 2023 - Version history
Received: May 13, 2022; Accepted: September 28, 2023 View PDF Abstract

Three sisters, born from consanguineous parents, manifested a unique Müllerian anomaly characterized by uterine hypoplasia with thin estrogen-unresponsive endometrium and primary amenorrhea, but with spontaneous tubal pregnancies. Through whole-exome sequencing followed by comprehensive genetic analysis, a missense variant was identified in the OSR1 gene. We therefore investigated OSR1/OSR1 expression in postpubertal human uteri, and the prenatal and postnatal expression pattern of Osr1/Osr1 in murine developing Müllerian ducts (MDs) and endometrium, respectively. We then investigated whether Osr1 deletion would affect MD development, using WT and genetically engineered mice. Human uterine OSR1/OSR1 expression was found primarily in the endometrium. Mouse Osr1 was expressed prenatally in MDs and Wolffian ducts (WDs), from rostral to caudal segments, in E13.5 embryos. MDs and WDs were absent on the left side and MDs were rostrally truncated on the right side of E13.5 Osr1–/– embryos. Postnatally, Osr1 was expressed in mouse uteri throughout their lifespan, peaking at postnatal days 14 and 28. Osr1 protein was present primarily in uterine luminal and glandular epithelial cells and in the epithelial cells of mouse oviducts. Through this translational approach, we demonstrated that OSR1 in humans and mice is important for MD development and endometrial receptivity and may be implicated in uterine factor infertility.

Graphical Abstract Introduction

The Müllerian ducts (MD) are paired embryonic structures that arise from the mesoderm-derived invaginations of the coelomic epithelium into the mesonephros and ultimately develop into segments of the female reproductive tract (FRT) — the oviducts, uterus, cervix, and upper part of the vagina (1, 2). Postnatally, MD derivatives function as the site of fertilization in many vertebrates, including humans and mice, and play fundamental roles in oocyte transport and nutrition, as well as in embryo development, thus determining reproductive success (3, 4).

Müllerian anomalies comprise a heterogeneous group of developmental defects that affect FRT anatomy and function, ranging from minor uterine abnormalities, such as septate and bicornuate uteri, to congenital absence of the uterus and vagina (1, 5). One of the most severe conditions in the spectrum of Müllerian anomalies in humans is Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), or uterovaginal agenesis, among the most common causes of primary amenorrhea. Approximately 1 in 4,500 live births have MRKH, representing 15% of women with primary amenorrhea. Rare cases of familial clustering and the association with other congenital defects, such as renal or skeletal malformations, have directed the search for a genetic basis of the disease (5, 6).

We studied a family in which 3 sisters, born from consanguineous parents, presented with a unique Müllerian anomaly characterized by uterine hypoplasia with a thin endometrium unresponsive to sex steroids and primary amenorrhea, but spontaneous tubal pregnancies. Our hypothesis was that a recessive genetic factor may have caused this familial phenotype, leading to disruption of MD development and patterning and a resultant reproductive tract developmental defect characterized by estrogen-resistant endometrial hypoplasia and impaired uterine embryo implantation. Through whole-exome sequencing (WES) followed by comprehensive genetic analysis, odd-skipped related 1 (OSR1) emerged as a candidate gene. OSR1 is the human homolog of the drosophila odd gene, which encodes a transcription factor expressed early during embryonic development in mice, beginning in the nascent intermediate mesoderm, and subsequently expressed in multiple mesenchymal derivatives in mice, including coelomic epithelium and the ur