Biallelic Germline BRCA1 Frameshift Mutations Associated with Isolated Diminished Ovarian Reserve - Archive ouverte HAL
Article Dans Une Revue International Journal of Molecular Sciences Année : 2024

Biallelic Germline BRCA1 Frameshift Mutations Associated with Isolated Diminished Ovarian Reserve

Marie Falampin
  • Fonction : Auteur
Abdelkader Heddar
Léa Guerrini-Rousseau
  • Fonction : Auteur
Maud Marchand
  • Fonction : Auteur
Iphigenie Cavadias
Nathalie Auger
Brigitte Bressac-de Paillerets
Laurence Brugieres
Bernard Lopez
  • Fonction : Auteur
Michel Polak
  • Fonction : Auteur
Filippo Rosselli
Micheline Misrahi

Résumé

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.

Dates et versions

hal-04800742 , version 1 (24-11-2024)

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Citer

Anne Helbling-Leclerc, Marie Falampin, Abdelkader Heddar, Léa Guerrini-Rousseau, Maud Marchand, et al.. Biallelic Germline BRCA1 Frameshift Mutations Associated with Isolated Diminished Ovarian Reserve. International Journal of Molecular Sciences, 2024, 25 (22), pp.12460. ⟨10.3390/ijms252212460⟩. ⟨hal-04800742⟩
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