Alternative titles; symbols
HGNC Approved Gene Symbol: PRICKLE3
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:49,174,802-49,186,373 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | {Leber hereditary optic neuropathy, modifier of} | 308905 | X-linked dominant | 3 |
In the study of a gene-rich region of the X chromosome, Fisher et al. (1997) identified a novel gene, PRICKLE3, which they called LMO6. LMO6 was predicted to encode a product of 407 amino acids with significant homology to proteins containing LIM domains, in particular, mouse testin (TES; 606085). The LIM domain is a cysteine-rich sequence motif that binds zinc atoms to form a specific protein-binding interface in protein-protein interactions. Like testin, the LMO6 product contains 3 such domains. Using RT-PCR, Fisher et al. (1997) amplified a 450-bp product spanning exons 5 to 7 of the LMO6 transcript from lymphoblastoid RNA. This confirmed that the LMO6 locus is transcribed and unlikely to be a pseudogene.
After transient expression of HA-tagged PRICKLE3 in HeLa cells, Yu et al. (2020) performed cellular fraction experiments that revealed enrichment of the exogenous PRICKLE3 within mitochondrial fractions as well as in the cytosol. The authors also observed ubiquitous expression of Prickle3 in mouse tissues and in various layers of mouse retina, as well as localization in mitochondria of mouse embryonic fibroblast cells.
Fisher et al. (1997) determined that the PRICKLE3 gene contains 8 exons.
Fisher et al. (1997) mapped the PRICKLE3 gene to chromosome Xp11.23-p11.22, within a 12.5-kb interval between the A4 (300112) and the SYP (313475) genes.
In HEK293T cell lines, Yu et al. (2020) demonstrated that PRICKLE3 and ATP synthase-8 (MTATP8; 516070) reciprocally immunoprecipitate. PRICKLE3 did not precipitate ATP5A (ATP5F1A; 164360), ATP5B (ATP5F1B; 102910), ATP5F (ATP5PB; 603270), ATPAF1 (608917), or UQCRC2 (191329), indicating that PRICKLE3 directly interacts with ATP synthase by specifically binding to ATP8.
In 3 Chinese families with maternally inherited Leber optic atrophy (LOAM; 308905) and the LHON11778A variant in the MTND4 gene (516003.0001), Yu et al. (2020) identified heterozygosity for a missense mutation in the PRICKLE3 gene (R53W; 300111.0001). All affected individuals carried both the MTND4 and the R53W mutations; individuals with only a single mutation had normal vision. The authors noted that the 3 Chinese families bearing both the R53W and LHON11778A mutations exhibited much higher penetrance and younger age at onset of optic neuropathy than families with only an LHON-associated mtDNA mutation, and suggested that the PRICKLE3 mutation is a rare variant that acts as an X-linked dominant susceptibility allele increasing the penetrance and expressivity of LHON-associated mtDNA mutation.
Using the CRISPR/Cas9 system, Yu et al. (2020) generated Prickle3 knockout mice. Enzymatic assays showed a 52% and 67% decrease in the activity of respiratory complex V in heterozygous and hemi-/homozygous mice, respectively, and altered assembly of complex V was also present in the mutant mice, as shown by 59% and 79% decreases of fully assembled ATP synthase. In addition, the mutant mice exhibited various reductions in levels of ATP8, ATP6 (516060), and ATP5B compared to wildtype mice. Retinas of Prickle3 +/- and -/- mice exhibited abnormal mitochondrial morphology, including vacuolation, fragmentation, and loss of cristae. Electroretinography (ERG) in the mutant mice showed that heterozygotes and hemi-/homozygotes developed retinal deficiency at 4 weeks of age. Stained retinal sections showed degeneration of retinal ganglion cells (RGCs), with reductions in numbers of RGCs of 22% and 39% in heterozygotes and homozygotes, respectively, compared to wildtype littermates. The mutant mice also had many fewer retinal neurofilaments than wildtype mice, and average total dendritic areas on RGCs in the heterozygous and homozygous mice were only 66% and 38% of wildtype, respectively. This dendritic pruning in Prickle3-deficient mice was supported by Western blot analysis showing reduced levels of postsynaptic protein Psd95 (602887) antibody in the mutants compared to wildtype mice. Retinal vasculature in Prickle3 -/+ and -/- mice at 8 weeks was tortuous and dilated, with increased branching. Full-field ERGs showed significantly reduced retinal function in the heterozygotes and hemi-/homozygotes, with responses that were 24 to 34% of those of wildtype mice. The authors suggested that the photoreceptor deficits were specific manifestations of the changes in RGCs caused by the deletion of Prickle3.
In 23 affected individuals from 3 Chinese families (SD1, XT, and AH) with maternally inherited Leber optic atrophy (LOAM; 308905), who were known to carry the LHON11778A variant in MTND4 (516003.0001), Yu et al. (2020) identified heterozygosity or hemizygosity for a c.157C-T transition (c.157C-T, NM_006150) in exon 3 of the PRICKLE3 gene, resulting in an arg53-to-trp (R53W) substitution at a highly conserved residue. All 23 affected individuals carried both the MTND4 and the R53W mutations; 4 individuals who carried only a single mutation had normal vision. Western blot analysis of lymphoblastoid cell lines carrying the R53W mutation, with or without the LHON11778A variant, showed an approximately 55% reduction in levels of PRICKLE3. The mutant protein was shown to localize normally to the mitochondria. Analysis of respiratory activity in cell lines with 1 or both of the variants indicated that the LHON11778A variant caused reduced activity of complex I, and R35W reduced activity of complex V. Levels of complex V monomer were reduced by approximately half in mutant cell lines carrying the R53W mutation, with or without the LHON11778A variant, whereas cells with the LHON11778A variant alone showed levels that were 95% of those of control cells. Measurement of oxygen consumption rates (OCRs) in various mutant and control cell lines showed that cells with only 1 of the variants displayed mild reductions in basal OCR and ATP-linked OCR, whereas more drastic reductions were observed in cell lines carrying both variants. Similarly, reductions in ATP production were greater in cells carrying both variants than in cells carrying only 1 of the variants.
Fisher, S. E., Ciccodicola, A., Tanaka, K., Curci, A., Desicato, S., D'Urso, M., Craig, I. W. Sequence-based exon prediction around the synaptophysin locus reveals a gene-rich area containing novel genes in human proximal Xp. Genomics 45: 340-347, 1997. [PubMed: 9344658] [Full Text: https://doi.org/10.1006/geno.1997.4941]
Yu, J., Liang, X., Ji, Y., Ai, C., Liu, J., Zhu, L., Nie, Z., Jin, X., Wang, C., Zhang, J., Zhao, F., Mei, S., Zhao, X., Zhou, X., Zhang, M., Wang, M., Huang, T., Jiang, P., Guan, M.-X. PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy. J. Clin. Invest. 130: 4935-4946, 2020. [PubMed: 32516135] [Full Text: https://doi.org/10.1172/JCI134965]