A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis
Ariella Weinberg-Shukron, … , Offer Gerlitz, David Zangen
Ariella Weinberg-Shukron, … , Offer Gerlitz, David Zangen
Published October 20, 2015
Citation Information: J Clin Invest. 2015;125(11):4295-4304. https://doi.org/10.1172/JCI83553.
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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 3

Impaired fertility and eggshell morphology in RFP-Nup107D364N mutant transgenic rescued flies.

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Impaired fertility and eggshell morphology in RFP-Nup107D364N mutant tra...
(A) The total number of eggs and progeny is reduced in RFP-Nup107D364N mutant transgenic rescued flies. The total number of laid eggs in transgenic rescued females is reduced by 47% in RFP-Nup107D364N mutant flies compared with that in RFP-Nup107WT flies (**P = 0.01). The number of progeny from transgenic rescued females is 7.2 times lower in RFP-Nup107D364N mutant flies compared with that in RFP-Nup107WT flies (***P = 0.0001). Hatch rate (progeny per total eggs) is only 12% in RFP-Nup107D364N mutant females compared with 45% in RFP-Nup107WT transgenic rescued females (P = 2.6E–7). The numbers of progeny or eggs are indicated above the bars. Results shown are the mean of >3 experiments, with >10 flies each. (B–E) Eggshell phenotypes. (B) Normal eggshell phenotype. (C–E) Representative images of aberrant eggshell phenotypes, including dorsal appendage and chorion defects: (C) lack of dorsal appendages, (D) misshapen dorsal appendages, and (E) aberrantly located dorsal appendages. Aberrant chorions appear far more translucent than the normally opaque chorion. Scale bar: 100 μm. (F) Quantification of aberrant eggshell phenotypes in RFP-Nup107D364N mutant transgenic rescued flies. In transgenic rescued female flies, the proportion of eggs with aberrant eggshell phenotypes was 69% (149 of 216) in RFP-Nup107D364N mutants compared with 25% (98 of 395) in RFP-Nup107WT flies (***P = 3.5E–14). The numbers of aberrant eggshell phenotypes are indicated above the bars. Results shown are the mean of >3 experiments, including >10 flies each. Statistical significance was assessed by a 2-tailed, unpaired Student’s t test.