Alternative titles; symbols
HGNC Approved Gene Symbol: PCLO
SNOMEDCT: 718609003;
Cytogenetic location: 7q21.11 Genomic coordinates (GRCh38): 7:82,754,012-83,162,884 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.11 | ?Pontocerebellar hypoplasia, type 3 | 608027 | Autosomal recessive | 3 |
Synaptic vesicles dock and fuse in the active zone of the plasma membrane at chemical synapses. The presynaptic cytoskeletal matrix (PCM), which is associated with the active zone and is situated between synaptic vesicles, is thought to be involved in maintaining the neurotransmitter release site in register with the postsynaptic reception apparatus. The cycling of synaptic vesicles is a multistep process involving a number of proteins (see 603215). Among the components of the PCM that orchestrate these events are bassoon (BSN; 604020), RIM (RBBP8; 604124), oboe (RIMS2; 606630), and piccolo (PCLO) (summary by Fenster et al., 2000).
By screening human brain cDNAs for those encoding proteins larger than 50 kD, Nagase et al. (1998) identified a partial cDNA encoding PCLO, which they called KIAA0559. RT-PCR analysis detected PCLO expression in kidney, with little or no expression in all other tissues tested.
By searching EST and genome databases with a murine Pclo cDNA probe, Fenster et al. (2000) identified genomic sequences and a brain-specific EST (KIAA0559) encoding human PCLO. The 5-prime terminus of the human sequence had yet to be determined, but the authors were able to deduce nearly the entire human PCLO protein. Sequence analysis indicated that the deduced 4,880-amino acid rat Pclo protein is 86% identical to human PCLO. In addition, PCLO shares significant amino acid sequence homology with BSN. BSN and PCLO share 10 homology regions, or PBH regions. PBH1 and PBH2 contain 2 double-zinc finger motifs. PBH4, PBH6, and PBH8 are likely to form coiled-coil structures. At the C terminus, unlike BSN but like RIM and Oboe, PCLO contains a PDZ domain and a C2 domain. The PCLO C2 domain contains all the asp residues required for calcium binding. Fenster et al. (2000) noted that PCLO also contains multiple proline-rich segments. Confocal microscopy analysis of cultured hippocampal neurons showed colocalization of BSN and PCLO at identical GABAergic and glutamatergic synapses, of synaptotagmin (see SYT1; 185605) and PCLO along dendritic profiles, and of PCLO zinc fingers and PRA1 (604925) at nerve terminals.
Using cAMP-GEFII (606058) as bait in a yeast 2-hybrid screen, Fujimoto et al. (2002) cloned mouse piccolo from an insulin-secreting cell line cDNA library. Northern blot analysis of mouse tissues revealed high levels in cerebrum and cerebellum and moderate levels in pituitary gland, pancreatic islets, and a pheochromocytoma-derived mouse cell line. In situ hybridization of mouse brain revealed piccolo mRNA expressed in cerebral cortex, hippocampus, olfactory bulb, cerebellar cortex, and pituitary gland. The distribution of piccolo mRNA largely overlapped that of cAMP-GEFII and Rim2 (606630) mRNA in tissues, cell lines, and mouse brain.
Ahmed et al. (2015) found expression of the PCLO gene in the developing human cortex, consistent with a role in synaptic function.
By comparing the human PCLO genomic sequence with the rat Pclo cDNA, Fenster et al. (2000) determined that the human PCLO gene contains at least 19 exons and spans over 350 kb.
Using radiation hybrid analysis, Nagase et al. (1998) mapped the PCLO gene to chromosome 7. Fenster et al. (2000) stated that the PCLO gene maps to chromosome 7q11.23-q21.1.
Gross (2015) mapped the PCLO gene to chromosome 7q21.11 based on an alignment of the PCLO sequence (GenBank BC001304) with the genomic sequence (GRCh38).
Fujimoto et al. (2002) characterized mouse piccolo and determined that it interacts with both cAMP-GefII and Rim2. In the presence of Ca(2+), the C2A domain of piccolo could homodimerize, it could interact with the C2A domain of Rim2, or it could bind the cAMP GefII-Rim2 complex. It did not bind cAMP-GefII directly. Treatment of pancreatic islets with antisense piccolo oligonucleotides inhibited insulin secretion induced by a cAMP analog and high glucose stimulation. Fujimoto et al. (2002) concluded that piccolo serves as a Ca(2+) sensor in exocytosis in pancreatic beta cells and that the formation of a cAMP-GEFII-RIM2 piccolo complex is required.
Takao-Rikitsu et al. (2004) found that Cast (ERC2; 617250), Rim1 (RIMS; 606629), Munc13-1 (UNC13A; 609894), Bassoon, and Piccolo formed the cytomatrix at the active zone (CAZ) protein complex in rat brain. Rim1 and Bassoon directly bound the C-terminal and central regions of Cast, respectively, forming a ternary complex. Piccolo, which is structurally related to Bassoon, also bound to the Bassoon-binding region of Cast. Microinjection of the Rim1- or Bassoon-binding regions of Cast impaired synaptic transmission in cultured superior cervical ganglion neurons. The Cast-binding domain of Rim1 or Bassoon also impaired synaptic transmission in cultured neurons. Takao-Rikitsu et al. (2004) concluded that CAST serves as a key component of the CAZ structure and is involved in neurotransmitter release by binding other CAZ proteins.
In 4 patients from a consanguineous Omani kindred with pontocerebellar hypoplasia type 3 (PCH3; 608027) originally reported by Rajab et al. (2003), Ahmed et al. (2015) identified a homozygous truncating mutation in the PCLO gene (R3542X; 604918.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but Ahmed et al. (2015) suggested that loss of PCLO may cause synaptic dysfunction and apoptosis, resulting in neuronal loss. Direct sequencing of the PCLO gene in over 500 exomes from individuals with various neurodevelopmental disorders did not identify any additional pathogenic mutations.
In 4 patients from a consanguineous Omani kindred with pontocerebellar hypoplasia type 3 (PCH3; 608027) originally reported by Rajab et al. (2003), Ahmed et al. (2015) identified a homozygous c.10624C-T transition (c.10624C-T, NM_033026.5) in exon 6 of the PCLO gene, resulting in an arg3542-to-ter (R3542X) substitution affecting both isoforms and predicted to eliminate both the PDZ and C2 domains. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project, Exome Variant Server, or Exome Aggregation Consortium databases, or in 122 Omani control chromosomes. Functional studies of the variant were not performed.
Ahmed, M. Y., Chioza, B. A., Rajab, A., Schmitz-Abe, K., Al-Khayat, A., Al-Turki, S., Baple, E. L., Patton, M. A., Al-Memar, A. Y., Hurles, M. E., Partlow, J. N., Hill, R. S., Evrony, G. D., Servattalab, S., Markianos, K., Walsh, C. A., Crosby, A. H., Mochida, G. H. Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology 84: 1745-1750, 2015. [PubMed: 25832664] [Full Text: https://doi.org/10.1212/WNL.0000000000001523]
Fenster, S. D., Chung, W. J., Zhai, R., Cases-Langhoff, C., Voss, B., Garner, A. M., Kaempf, U., Kindler, S., Gundelfinger, E. D., Garner, C. C. Piccolo, a presynaptic zinc finger protein structurally related to bassoon. Neuron 25: 203-214, 2000. [PubMed: 10707984] [Full Text: https://doi.org/10.1016/s0896-6273(00)80883-1]
Fujimoto, K., Shibasaki, T., Yokoi, N., Kashima, Y., Matsumoto, M., Sasaki, T., Tajima, N., Iwanaga, T., Seino, S. Piccolo, a Ca(2+) sensor in pancreatic beta-cells: involvement of cAMP-GEFII-Rim2-piccolo complex in cAMP-dependent exocytosis. J. Biol. Chem. 277: 50497-50502, 2002. [PubMed: 12401793] [Full Text: https://doi.org/10.1074/jbc.M210146200]
Gross, M. B. Personal Communication. Baltimore, Md. 6/30/2015.
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
Rajab, A., Mochida, G. H., Hill, A., Ganesh, V., Bodell, A., Riaz, A., Grant, P. E., Shugart, Y. Y., Walsh, C. A. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 60: 1664-1667, 2003. [PubMed: 12771259] [Full Text: https://doi.org/10.1212/01.wnl.0000068548.58498.41]
Takao-Rikitsu, E., Mochida, S., Inoue, E., Deguchi-Tawarada, M., Inoue, M., Ohtsuka, T., Takai, Y. Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release. J. Cell Biol. 164: 301-311, 2004. [PubMed: 14734538] [Full Text: https://doi.org/10.1083/jcb.200307101]