The Expanding Phenotypic Spectrum of NUP188 Variants Points Toward Multiple Biological Pathways

In 2020, Molecular Syndromology published a report of 2 female children sharing several clinical phenotypes who died soon after birth of respiratory failure [Sandestig et al., 2020]. Shortly thereafter, a series of 6 females sharing the same set of clinical phenotypes and all dying of respiratory failure was published [Muir et al., 2020]. The disorder, characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, a typical facial gestalt, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and early death, became known as Sandestig-Stefanova syndrome (OMIM #618804). The Sandestig-Stefanova syndrome is due to biallelic variations of the NUP188 gene. In the current issue of Molecular Syndromology, a ninth, this time a male, patient with Sandestig-Stefanova syndrome is described [Korulmaz et al., 2022]. This boy, showing the typical features of Sandestig-Stefanova syndrome, also had ambiguous genitalia, hypospadias, undescended testis, immunodeficiency, congenital hypothyroidism, and biotinidase deficiency [Korulmaz et al., 2022].

While this case broadens the clinical spectrum of Sandestig-Stefanova syndrome with typical male phenotypes, it also poses the conceptual challenge to subsume all phenotypes under biallelic variations of the NUP188 gene. Phenotypes as microcephaly, trigonocephaly, and hypertelorism may point toward a craniosynostosis syndrome, yet no nucleoporin gene has been linked to any of the known craniosynostosis syndromes [Goos and Mathijssen, 2019]. In addition, no nucleoporin genes have been identified by large-scale gene discovery studies [Poot, 2019]. Likewise, hypospadias, undescended testicles, and ambiguous genitalia have thus far been thought to result from mutations affecting the hedgehog, FGF, BMP, and WNT signaling pathways or in genes participating in the metabolism of androgens and estrogens [Bouty et al., 2015; Piñeyro-Ruiz et al., 2020]. Thus, the urogenital phenotypes in this boy with biallelic NUP188 variants are novel, highly unexpected, and puzzling.

The clear, albeit variable, cardiovascular phenotypes of the thus far described patients with Sandestig-Stefanova syndrome are consistent with an alternative mechanism(s) for the phenotypic effects of NUP188 variants [Muir et al., 2020; Sandestig et al., 2020; Korulmaz et al., 2022]. The original patients both showed a ventricular septal defect, while 5 of the 6 patients described by Muir et al. [2020] had cardiac abnormalities including a bicuspid aortic valve, a patent ductus arteriosus, and a partial anomalous pulmonary venous return. The male patient described by Korulmaz et al. [2022] had hypertrophy of the left ventricle. A mother and her child with a heterozygous truncating splice donor variant in NUP188 had both a mitral valve prolapse [Haskell et al., 2017]. In contrast, a patient with a duplication encompassing the full NUP188 gene and transposition of the great arteries has been found in a screen for abnormalities in left-right body patterning [Fakhro et al., 2011].

While patients with congenital cardiac abnormalities often carry variants in genes involved in cell signaling pathways, such as Notch, WNT/β-Catenin, BMP, Sonic Hedgehog, Ras/MAPK or VEGF, or transcription factors of the NKX2-5, GATA, T-Box, Forkhead and nuclear receptor families, in some patients also genes encoding chromatin modifiers, cilia related proteins, and cilia-transduced cell signaling pathways were affected [Williams et al., 2019]. In a recessive forward genetic screen in fetal mice for congenital heart disorders almost half of the affected genes proved to be encoding for the cilium and cilia transduced cell signaling pathways [Li et al., 2015]. At first sight, the NUP188 gene does not seem to fit into any of these categories. Yet, in a recent study, the Nup188 protein turned out to localize to the basis of cilia [Del Viso et al., 2016]. Morpholino-based knockdown of Nup188 or its binding partner Nup93 in Xenopus leads to a loss of cilia during embryonic development, while the function of the nuclear pore complex remained largely intact [Del Viso et al., 2016]. During mitosis, Nup188 localizes to the spindle poles [Itoh et al., 2013]. Upon Nup188 depletion in mitotic cells, chromosomes fail to align to the metaphase plate, which activates the spindle assembly checkpoint and causes mitotic arrest [Itoh et al., 2013]. These findings suggest that the Nup188 protein may have, apart from its involvement in the nuclear pore complex, other cellular localizations and hence functions.

While biallelic loss of function variants of NUP188 provoke the Sandestig-Stefanova syndrome, which involves, among other phenotypes, a ventricular septal defect, a bicuspid aortic valve, or a patent ductus arteriosus, heterozygous truncating variants lead to a dominantly inheritable mitral valve prolapse [Haskell et al., 2017; Muir et al., 2020; Sandestig et al., 2020; Korulmaz et al., 2022]. In contrast, duplication of the whole NUP188 gene results in defects of left-right patterning [Fakhro et al., 2011]. These findings suggest that depending on the type of variant affecting NUP188 distinct pathogenic mechanisms are activated, which warrants further scrutiny. In addition, detailed clinical descriptions of patients with either single nucleotide or copy number variants of NUP188 like the case report discussed here will further enhance our understanding of the multiple functions of the NUP188 protein and its partners.

Martin Poot