A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.
Ovarian development and maintenance are poorly understood; however, diseases that affect these processes can offer insights into the underlying mechanisms. XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries, with subsequent lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism. Here, we report an extended consanguineous family of Palestinian origin, in which 4 females exhibited XX-GD. Using homozygosity mapping and whole-exome sequencing, we identified a recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A, p.D447N). This mutation segregated with the XX-GD phenotype and was not present in available databases or in 150 healthy ethnically matched controls. NUP107 is a component of the nuclear pore complex, and the NUP107-associated protein SEH1 is required for oogenesis in Drosophila. In Drosophila, Nup107 knockdown in somatic gonadal cells resulted in female sterility, whereas males were fully fertile. Transgenic rescue of Drosophila females bearing the Nup107D364N mutation, which corresponds to the human NUP107 (p.D447N), resulted in almost complete sterility, with a marked reduction in progeny, morphologically aberrant eggshells, and disintegrating egg chambers, indicating defective oogenesis. These results indicate a pivotal role for NUP107 in ovarian development and suggest that nucleoporin defects may play a role in milder and more common conditions such as premature ovarian failure.
Ariella
A
Weinberg-Shukron
Paul
P
Renbaum
Rachel
R
Kalifa
Sharon
S
Zeligson
Ziva
Z
Ben-Neriah
Amatzia
A
Dreifuss
Amal
A
Abu-Rayyan
Noa
N
Maatuk
Nilly
N
Fardian
Dina
D
Rekler
Moien
M
Kanaan
Abraham O
AO
Samson
Ephrat
E
Levy-Lahad
Offer
O
Gerlitz
David
D
Zangen
D000293:Adolescent; D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified; D020346:Aquaporins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003241:Consanguinity; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics; D005260:Female; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics*; D006801:Humans; D007247:Infertility, Female / Q000235:genetics; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009024:Morphogenesis; D046912:Multiprotein Complexes; D020125:Mutation, Missense; D028861:Nuclear Pore Complex Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D009866:Oogenesis / Q000235:genetics; D010053:Ovary / Q000473:pathology*; D010063:Ovum / Q000473:pathology; D010375:Pedigree; D011487:Protein Conformation
D020346:Aquaporins; D029721:Drosophila Proteins; D046912:Multiprotein Complexes; C512772:NUP107 protein, human; D028861:Nuclear Pore Complex Proteins; C538722:Nup107 protein, Drosophila