Centrosome and ciliary abnormalities in fetal akinesia deformation sequence human fibroblasts

Abstract

Ciliopathies are clinical disorders of the primary cilium with widely recognized phenotypic and genetic heterogeneity. Here we found that impaired ciliogenesis in fibroblasts derived from individuals with fetal akinesia deformation sequence (FADS).FADS refers to a broad spectrum of neuromuscular disorders arising from impaired fetal movement. We show that cells derived from two FADS individuals, one with an unknown genetic cause and one with bi-allelic pathogenic variants in RAPSN, have shorter and less primary cilia (PC), in association with alterations in posttranslational modifications in α -tubulin. Similarly, siRNA-mediated depletion of two known FADS proteins, the scaffold protein rapsyn and the nucleoporin NUP88, resulted in defective PC formation. Consistent with a role in ciliogenesis, rapsyn and NUP88 localized to centrosomes and PC. By proximity-ligation assays, we show that rapsyn and NUP88 are interacting and that both proteins are connecting to all three tubulin isoforms (α, ß, and γ ). The rapsyn-NUP88 interface, as well as their contact to microtubules, is perturbed in the examined FADS cells, similarly to their contact to microtubules. We suggest that the perturbed rapsyn-NUP88-tubulin interface leads to defects in PC formation and that defective ciliogenesis contributes to the pleiotropic defects seen in FADS.

Bi-allelic loss-of-function variants inKIF21Acause severe fetal akinesia with arthrogryposis multiplex

“…These include ion channels or pumps, receptors or modulators, inborn errors of metabolism, factors involved in transcription and translation, cell cycle, cell signalling/secretion as well as motor proteins or protein trafficking 6. From an organelle perspective, a postulated mechanism underlying FA is impaired ciliogenesis,33 which is interesting, as KIFs are known to fulfil an essential role in ciliogenesis and cilia function 23. In addition, primary cilia-driven signalling regulates growth cone dynamics and axonal tract development,34 and several genes linked to arthrogryposis, such as AUTS2, CBL, DNM2, IGHMBP2, KIF5C, SETX, SNAP25 and TOR1A function in growth cone regulation 35.…”

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

“…Moreover, NUP88 interacts with the focal adhesion protein paxillin and together with other FADS proteins regulates actin‐myosin organisation [148]. The interaction between NUP88 and paxillin is abolished by FADS‐related mutations in NUP88 and depletion of NUP88 perturbs actin cytoskeleton organisation [148], supporting the hypothesis that a loss of functional NUP88 induces cytoskeletal anomalies and hence may lead to the abnormal muscular contraction seen in FADS individuals.…”