Mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence

Fetal akinesia deformation sequence (FADS) comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. FADS often results from mutations in genes affecting the muscle nicotinic acetylcholine receptor (AChR). Here we describe mutations in NUP88 coding for the nucleoporin NUP88 as a novel cause of lethal FADS in two families. A homozygous c.1300G>T (p.D434Y) mutation in two individuals and a compound heterozygous mutation c.1525C>T (p.R509*) and c1899_1901del (p.E634del) in one individual were found. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Loss of NUP88 coincides with aberrant levels and localization of rapsyn, a key regulator of AChR clustering. These findings expand our understanding of the molecular events causing FADS and suggest that variants in NUP88 should be investigated in cases of FADS.