期刊
HUMAN MOLECULAR GENETICS
卷 23, 期 14, 页码 3657-3665出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu074
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资金
- Laboratoire Lilly France
- Agence Nationale de la Recherche-GIS Institut des Maladies Rares
- March of Dimes Foundation Research Grant [1-FY07-490]
- EuroDSD in the European Community's Seventh Framework Programme FP7 [201444]
- Projet Blanc Institut Pasteur/Assistance Publique-Hopitaux de Paris [295097]
- GM_NCD_in_Co-Reinforcing IPT capacities in Genomic Medicine, Non Communicable Diseases Investigation and international cooperation as part of the EU [FP7-INCO-2011-6]
- Actions concertees Inter-Pasteuriennes [ACIP A16-2013]
- Franco-Egyptian AIRD-STDF grant
In recent years, considerable advances have been made in our understanding of genetics of mammalian gonad development; however, the underlying genetic aetiology in the majority of patients with 46,XY disorders of sex development (DSD) still remains unknown. Based on mouse models, it has been hypothesized that haploinsufficiency of the Friend of GATA 2 (FOG2) gene could lead to 46,XY gonadal dysgenesis on specific inbred genetic backgrounds. Using whole exome sequencing, we identified independent missense mutations in FOG2 in two patients with 46,XY gonadal dysgenesis. One patient carried a non-synonymous heterozygous mutation (p.S402R), while the other patient carried a heterozygous p.R260Q mutation and a homozygous p.M544I mutation. Functional studies indicated that the failure of testis development in these cases could be explained by the impaired ability of the mutant FOG2 proteins to interact with a known regulator of early testis development, GATA4. This is the first example of mutations in the coding sequence of FOG2 associated with 46,XY DSD in human and adds to the list of genes in the human known to be associated with DSD.
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