Cytoplasmic carboxypeptidase 5 regulates tubulin glutamylation and zebrafish cilia formation and function

Abstract

Zebrafish have four tubulin deglutamylases: Ccp1, Ccp2, Ccp5, and Ccp6. Except for ccp1, all deglutamylase genes are expressed during ciliogenesis in zebrafish. Only loss of ccp5 induces cilia hyperglutamylation and the complete spectrum of ciliopathy phenotype. ccp5 knockdown can bypass Fleer/Ift70 or Ift88 deficiency in zebrafish to form multicilia.

Exome Sequencing RevealsAGBL5as Novel Candidate Gene and Additional Variants for Retinitis Pigmentosa in Five Turkish Families

“…One study reported a smaller eye size in CCP5 zebrafish morphants, 14 and knock down of Ccp5 was found to increase cilia tubulin glutamylation which led to ciliopathy phenotypes and interferred multicilia motility. 13 In our study we were able to demonstrate the expression of RNA and protein in human retina. Moreover, AGBL5 expression was also found in mouse retina where it was located in the inner nerve fiber and inner ganglion cell layer (GCL), as well as in the inner (IPL) and outer (OPL) plexiform layers.…”

“…In zebrafish, Ccp5 was found to be crucial for the embryonic development and ciliogenesis. 13,14 We therefore suggest that AGBL5 expression and thus deglutaminase function could be essential for developmental processes in the mouse and possibly in humans. The high RNA expression levels of Agbl5 in testis of P10 and P28 mice are in line with previously reported AGTBP1 expression where stronger antibody signals were detected in mouse testis from P18 onwards when compared to earlier stages.…”

“…Besides sequence variations of highly probable pathogenic relevance in known candidate genes for RP, we identified a novel homozygous missense mutation in a gene so far not connected to human disease (AGBL5) in one of the families displaying autosomal recessive inheritance. Previous studies investigated the characteristics of the encoded protein in zebrafish 13,14 and mice, 15,16 where it is called CCP5 (zebrafish, mice) or AGBL5 (mice). Moderate expression of Agbl5 was confirmed in mouse eye and brain as well as its abundant presence in testis.…”

Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies

“…Knockdown of ccp5 in zebrafish leads to a classic ciliopathy phenotype. 27 The biological plausibility of CDH16, encoding Ksp-Cadherin, is less clear, although other cadherins (PCDH15, CDH23, and CDH3) are known to cause RD. In the absence of an independent mutation in AGBL5 and CDH16, their candidacy remains to be proven.…”

Mutations in AGBL5, Encoding α-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa

“…Furthermore, mutation of the active site of the carboxypeptidase domain causes abnormal cilia development in zebrafish. 14 The protein-truncating variants, that is, p.(Trp592*) and p.(Ala502-Glyfs*15), are expected to result in complete loss of function due to premature translation termination and NMD.…”