ZRSR2

Cilia effects upon perturbation of ZRSR2

Loss-of-function effect:

Longer cilia

Ciliogenesis screen results (3 screens)

• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-3.68) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680
• Pusapati et al. 2018 (CRISPR) [CRISPR]: Positive Regulator (Hh signaling, neg_rank=979, lfc=-0.78) PMID:30270045

Phenotypes

Human ciliopathy phenotype:

X-linked recessive Orofaciodigital Syndrome with brain anomalies: oral, facial, digital anomalies, plus alobar holoprosencephaly to pituitary anomalies, median cleft lip/palate, congenital heart defects. 8 affected males from 6 families (Hannes 2024).

Ciliopathy associations

• Orofaciodigital Syndrome

References: PMID:38158857

Subcellular localization

nucleus, minor spliceosome

References: PMID:38158857

Functional category

• Ciliary assembly/disassembly

Function

ZRSR2 (zinc-finger, CCCH-domain, RNA-binding-motif, serine/arginine-rich protein 2; also known as U2AF1-RS2 or URP) is a splicing factor essential for 3-prime splice site recognition of U12-type minor introns and assembly of the early minor spliceosome complex. Germline frameshift variants in the last exon of ZRSR2 cause a novel X-linked recessive type of Orofaciodigital Syndrome (OFD) with brain anomalies ranging from alobar holoprosencephaly to pituitary defects (Hannes et al. 2024 HGG Advances). Patient mutations: NM_005089.4:c.1207_1208del p.(Arg403GlyfsTer24) in 7 affected males from 5 unrelated families (de novo or X-linked inherited), and c.1211_1212del p.(Gly404GlufsTer23) in 2 affected males from 1 family. Mechanism: defective U12-type intron splicing in patient lymphoblastoid and fibroblast cells, with enrichment of minor intron retention affecting ciliopathy-related genes including TMEM107 and CIBAR1. Patient primary fibroblasts display abnormally elongated primary cilia. Confirms minor spliceosome involvement in primary cilia formation, paralleling the SCNM1-OFD phenotype (Iturrate 2022).