In vitro modeling and rescue of ciliopathy associated with IQCB1/NPHP5 mutations using patient-derived cells

• DOI: 10.1016/j.stemcr.2022.08.006
• Publication Date: 2022-09-08T14:28:57Z
• Authors: Kamil Kruczek; Zepeng Qu; Emily Welby; Hiroko Shimada; Suja Hiriyanna; Milton A. English; Wadih M. Zein; Brian P. Brooks; Anand Swaroop
• Keywords: Ciliopathy

Mutations in the IQ calmodulin-binding motif containing B1 (IQCB1)/NPHP5 gene encoding ciliary protein nephrocystin 5 cause early-onset blinding disease Leber congenital amaurosis (LCA), together with kidney dysfunction Senior-Løken syndrome. For vitro modeling, we obtained dermal fibroblasts from patients NPHP5-LCA that were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated retinal pigment epithelium (RPE) organoids. Patient RPE demonstrated aberrantly elongated axonemes. Organoids revealed impaired development of outer segment structures, which are modified primary cilia, mislocalization visual pigments to photoreceptor cell soma. All patient-derived showed reduced levels CEP290 protein, a critical cilia transition zone component interacting NPHP5, providing plausible mechanism for aberrant gating cargo transport. Disease phenotype organoids could be rescued by adeno-associated virus (AAV)-mediated IQCB1/NPHP5 augmentation therapy. Our studies thus establish human model path treatment NPHP5-LCA.