Germline NUP98 Variants in Two Siblings with a Rothmund–Thomson-Like Spectrum: Protein Functional Changes Predicted by Molecular Modeling

Abstract

Two adult siblings born to first-cousin parents presented a clinical phenotype reminiscent of Rothmund–Thomson syndrome (RTS), implying fragile hair, absent eyelashes/eyebrows, bilateral cataracts, mottled pigmentation, dental decay, hypogonadism, and osteoporosis. As the clinical suspicion was not supported by the sequencing of RECQL4, the RTS2-causative gene, whole exome sequencing was applied and disclosed the homozygous variants c.83G>A (p.Gly28Asp) and c.2624A>C (p.Glu875Ala) in the nucleoporin 98 (NUP98) gene. Though both variants affect highly conserved amino acids, the c.83G>A looked more intriguing due to its higher pathogenicity score and location of the replaced amino acid between phenylalanine-glycine (FG) repeats within the first NUP98 intrinsically disordered region. Molecular modeling studies of the mutated NUP98 FG domain evidenced a dispersion of the intramolecular cohesion elements and a more elongated conformational state compared to the wild type. This different dynamic behavior may affect the NUP98 functions as the minor plasticity of the mutated FG domain undermines its role as a multi-docking station for RNA and proteins, and the impaired folding can lead to the weakening or the loss of specific interactions. The clinical overlap of NUP98-mutated and RTS2/RTS1 patients, accounted by converging dysregulated gene networks, supports this first-described constitutional NUP98 disorder, expanding the well-known role of NUP98 in cancer.

Non-classical functions of nuclear pore proteins in ciliopathy

“…Depleting representative components of the central transport channel (Nup62) has no discernible effect on cardiac looping in Xenopus ( Marquez et al, 2021 ). Although mutations in NUP62 and NUP98 have been identified in patients with autosomal recessive infantile bilateral striatal necrosis and Rothmund–Thomson-like spectrum ( olombo et al, 2023 ; Basel-Vanagaite et al, 2006 ), evidence of a cilia-related connection to these diseases has not been reported.…”

Rare Diseases: Implementation of Molecular Diagnosis, Pathogenesis Insights and Precision Medicine Treatment

“…The study by Colombo et al [15] attests to how combined WES and molecular modeling can reduce the diagnostic gap of RD, leading to the discovery of novel ultra-rare diseases. Whole exome sequencing of two siblings presenting a phenotype reminiscent of Rothmund Thomson syndrome (RTS) [16] disclosed two linked homozygous missense variants, inherited from healthy first cousin parents, in exons 3 and 20 of the nucleoporin 98 (NUP98) gene.…”