NUP107 – 46,XX Gonadal Dysgenesis

XX,XX gonadal dysgenesis (46,XX‐GD) is a rare autosomal recessive disorder characterized by underdeveloped, dysfunctional ovaries, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism (HP:0000786; HP:0000013; HP:0000815).

An extended consanguineous Palestinian family segregating four affected females was studied by homozygosity mapping and whole‐exome sequencing, identifying a homozygous NUP107 missense variant, c.1339G>A (p.Asp447Asn), that co‐segregated with 46,XX‐GD and was absent from public databases and 150 ethnically matched controls (4 probands) (PMID:26485283).

The variant c.1339G>A (p.Asp447Asn) affects a highly conserved residue in the central scaffold of the nuclear pore complex and follows an autosomal recessive inheritance pattern with complete segregation in the kindred.

Functional modeling in Drosophila demonstrated that Nup107 knockdown in somatic gonadal cells causes complete female sterility, while transgenic rescue with the orthologous Nup107D364N mutation (corresponding to human p.Asp447Asn) resulted in drastically reduced progeny, aberrant eggshell morphology, and disintegrating egg chambers, confirming a critical role in oogenesis (PMID:26485283).

A separate study described a novel NUP107 variant, c.1063C>T (p.Arg355Cys), in two sisters with hypergonadotropic hypogonadism and generated a CRISPR/Cas9 mouse model, in which homozygous R355C or a nine–base‐pair deletion led to female subfertility; however, pathogenicity remains classified as uncertain (PMID:29363275).

Together, genetic and experimental data support a loss‐of‐function mechanism for NUP107 in ovarian development. Genetic testing for NUP107 variants should be considered in 46,XX gonadal dysgenesis to inform diagnosis and reproductive counseling.

References

• The Journal of clinical investigation • 2015 • A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis. PMID:26485283
• Molecular genetics & genomic medicine • 2018 • Functional study of a novel missense single-nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency. PMID:29363275

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