NUP88 – Fetal Akinesia Deformation Sequence

Biallelic variants in the nucleoporin gene NUP88 have been implicated in lethal fetal akinesia deformation sequence, a disorder of impaired fetal movement associated with congenital contractures and neurodevelopmental defects. The association is supported by identification of pathogenic NUP88 alleles in two unrelated families and comprehensive functional validation in vertebrate and cellular models.

Genetic analysis of two affected fetuses revealed compound heterozygous variants including a frameshift deletion and a nonsense change consistent with loss of function. One representative allele, c.1899_1901del (p.Glu634del), co-segregates with disease in both parents and was absent from population databases ([PMID:30543681]). The AR inheritance pattern is clear and no additional unrelated segregation data are currently described.

Overall clinical validity is categorized as Strong based on biallelic variants in two unrelated families ([PMID:30543681]) and reproducible functional concordance. Genetic evidence is Moderate given two probands from independent pedigrees with LoF and missense changes in NUP88 ([PMID:30543681]).

Functional studies in zebrafish demonstrate that nup88 disruption causes pleiotropic developmental defects including locomotor impairment and neuromuscular junction abnormalities mirroring human FADS; these phenotypes are fully rescued by wild-type but not mutant NUP88 ([PMID:30543681]). In human and mouse cell lines and fetal muscle tissue, NUP88 depletion disrupts rapsyn localization at the acetylcholine receptor, elucidating a mechanism of impaired neuromuscular signaling.

Functional evidence is rated Moderate due to robust in vivo modeling and rescue, combined with cellular assays linking NUP88 deficiency to neuromuscular junction pathology ([PMID:30543681]). No conflicting reports have been published to date.

Together, these data integrate genetic and experimental findings to establish NUP88 as a cause of autosomal recessive fetal akinesia deformation sequence. Genetic testing for NUP88 variants can inform prenatal diagnosis and reproductive counseling for families at risk.

References

• PLoS Genetics • 2018 • Biallelic mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence PMID:30543681

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