A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis
Ariella Weinberg-Shukron, Paul Renbaum, Rachel Kalifa, Sharon Zeligson, Ziva Ben-Neriah, Amatzia Dreifuss, Amal Abu-Rayyan, Noa Maatuk, Nilly Fardian, Dina Rekler, Moien Kanaan, Abraham O. Samson, Ephrat Levy-Lahad, Offer Gerlitz, David Zangen
Ariella Weinberg-Shukron, Paul Renbaum, Rachel Kalifa, Sharon Zeligson, Ziva Ben-Neriah, Amatzia Dreifuss, Amal Abu-Rayyan, Noa Maatuk, Nilly Fardian, Dina Rekler, Moien Kanaan, Abraham O. Samson, Ephrat Levy-Lahad, Offer Gerlitz, David Zangen
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Research Article Endocrinology Genetics

A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis

Abstract

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.

Authors

Ariella Weinberg-Shukron, Paul Renbaum, Rachel Kalifa, Sharon Zeligson, Ziva Ben-Neriah, Amatzia Dreifuss, Amal Abu-Rayyan, Noa Maatuk, Nilly Fardian, Dina Rekler, Moien Kanaan, Abraham O. Samson, Ephrat Levy-Lahad, Offer Gerlitz, David Zangen

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Figure 1

An extended consanguineous family with XX-GD.

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An extended consanguineous family with XX-GD. (A) Family pedigree. The p...
(A) Family pedigree. The proband is indicated by an arrow. Pedigree numbers of individuals are indicated above the symbols and ages are indicated beneath. The NUP107 c.1339G>A (p.D447N) WT (G) and the variant (A) nucleotides are indicated. (B) Sanger sequencing of the NUP107 c.1339G>A variant in genomic DNA of WT, heterozygous, and homozygous individuals. Nucleotides are indicated above the sequences, and amino acid residues are marked below; the c.1339G>A variant position is circled in red. (C) Evolutionary conservation of the NUP107 residue D447. The nucleotide sequence flanking c.1339 is indicated above, with the mutated nucleotide in red, and corresponding residues in various species are shown below. The region including D447 is highly conserved, and D447 (highlighted by vertical red lines) is conserved in all species shown, including in Drosophila melanogaster, as well as in all other Drosophila species (data not shown). (D and E) Structural modeling of the NUP107 p.D447N mutation. (D) Illustration of the 3D arrangement of the human NUP107 complex within the NPC scaffold on the nuclear membrane (colored peach). All 16 copies of the human NUP107 subcomplex within the cytoplasmic ring are shown. The inner and outer subcomplexes are colored green and blue, respectively, and adjacent nucleoporins and subcomplexes are colored purple (adapted from ref. 24). (E) Model of the NUP107 NTD, with D447 colored red and K278 and R355 colored purple. This figure was prepared using PyMol (71). (F) D447 forms salt bridges with K278 and R355. The salt bridges between D447 and K278 and R355 are indicated by broken yellow lines. The N447 mutant changes the overall charge of NUP107 and abolishes these salt bridges. This figure was prepared using PyMol (71).