| Title: |
Biallelic Germline BRCA1 Frameshift Mutations Associated with Isolated Diminished Ovarian Reserve |
| Authors: |
Helbling-Leclerc, Anne; Falampin, Marie; Heddar, Abdelkader; Guerrini-Rousseau, Léa; Marchand, Maud; Cavadias, Iphigenie; Auger, Nathalie; Bressac-de Paillerets, Brigitte; Brugieres, Laurence; Lopez, Bernard; Polak, Michel; Rosselli, Filippo; Misrahi, Micheline |
| Contributors: |
Intégrité du génome et cancers (IGC); École Pratique des Hautes Études (EPHE); Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS); Centre des Pathologies gynécologiques Rares CHU Necker; Hôpital Necker - Enfants Malades AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Hôpital Bicêtre GHU AP-HP. Université Paris-Saclay, Le Kremlin-Bicêtre; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-GHU AP-HP. Université Paris Saclay; Département de cancérologie de l'enfant et de l'adolescent Gustave Roussy; Institut Gustave Roussy (IGR); Département de biologie et pathologie médicales Gustave Roussy; Dynamique des cellules tumorales (TCD); Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay; Institut Cochin (IC UM3 (UMR 8104 / U1016)); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité) |
| Source: |
ISSN: 1661-6596. |
| Publisher Information: |
CCSD; MDPI |
| Publication Year: |
2024 |
| Collection: |
Inserm: HAL (Institut national de la santé et de la recherche médicale) |
| Subject Terms: |
[SDV]Life Sciences [q-bio] |
| Description: |
International audience ; The use of next-generation sequencing (NGS) has recently enabled the discovery of genetic causes of primary ovarian insufficiency (POI) with high genetic heterogeneity. In contrast, the causes of diminished ovarian reserve (DOR) remain poorly understood. Here, we identified by NGS and whole exome sequencing (WES) the cause of isolated DOR in a 14-year-old patient. Two frameshift mutations in BRCA1 (NM_007294.4) were found: in exon 8 (c.470_471del; p.Ser157Ter) and in exon 11 (c.791_794del, p.Ser264MetfsTer33). Unexpectedly, the patient presented no signs of Fanconi anemia (FA), i.e., no developmental abnormalities or indications of bone marrow failure. However, high chromosomal fragility was found in the patient’s cells, consistent with an FA diagnosis. RT-PCR and Western-blot analysis support the fact that the c. 791_794del BRCA1 allele is transcribed and translated into a shorter protein (del11q), while no expression of the full-length BRCA1 protein was found. DNA damage response (DDR) studies after genotoxic agents demonstrate normal activation of the early stages of the DDR and FANC/BRCA pathway. This is consistent with the maintenance of residual repair activity for the del11q BRCA1 isoform. Our observation is the first implication of bi-allelic BRCA1 mutations in isolated ovarian dysfunction or infertility in humans, without clinical signs of FA, and highlights the importance of BRCA1 in ovarian development and function. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.3390/ijms252212460 |
| Availability: |
https://hal.science/hal-04800742; https://hal.science/hal-04800742v1/document; https://hal.science/hal-04800742v1/file/ijms-25-12460-v2.pdf; https://doi.org/10.3390/ijms252212460 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.9D8985F6 |
| Database: |
BASE |