ESPEYB16 6. DSD and Gender Dysphoria New Functions of (Old) Genes (5 abstracts)
6.4. Essential role of BRCA2 in ovarian development and function
Weinberg-Shukron A , Rachmiel M , Renbaum P , Gulsuner S , Walsh T , Lobel O , Dreifuss A , Ben-Moshe A , Zeligson S , Segel R , Shore T , Kalifa R , Goldberg M , King MC , Gerlitz O , Levy-Lahad E & Zangen D
N Engl J Med. 2018 Sep 13;379(11):1042–1049.
doi: 10.1056/NEJMoa1800024. PMID: 30207912
This case report describes two sisters with 46,XX karyotype and hypergonadotropic hypogonadism – i.e. ovarian dysgenesis. They had normal general development and normal cognition. With estrogen replacement they developed normal sex characteristics and reached their target height. Whole genome sequencing showed that they were compound heterozygous for truncating mutations in the BRCA2 gene resulting in reduced amounts of BRCA2 protein.
Functional studies of chromosomal breakage measured in lymphocytes exposed to mitomycin C showed 50 times as many breaks in peripheral lymphocytes from these sisters compared to controls. Hence, the mutation also resulted in impaired DNA repair. This was consistent with the medical history of this family. One of the sisters was a long-term survivor of acute myeloid leukaemia 5 years of age, and one brother had died of leukemia at age 13. The mother was diagnosed with ovarian cancer stage III on ultrasound by an assessment initiated by the genetic study. The BRCA2 defect as the cause of the ovarian dysgenesis was confirmed via studies in a drosophila model, in which a null mutation in Dmbrca2, the fly ortholog of BRCA2, caused sterility and gonadal dysgenesis in both sexes.
The findings in this paper add important contributions to our understanding of ovarian development and the causes of ovarian dysgenesis. Autosomal dominant BRCA2 mutations are a well-established cause of very strong susceptibility to breast and ovarian cancers due to impaired ability to repair DNA double-strand breaks. The current findings show that this mechanism is also essentially involved in ovarian development. In addition, it adds a new clinical perspective since an increased cancer risk may be linked to ovarian dysgenesis in some cases.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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