Expanding the spectrum of phenotypes for MPDZ: Report of four unrelated families and review of the literature.

MPDZ, a gene with diverse functions mediating cell-cell junction interactions, receptor signaling, and binding multivalent scaffold proteins, is associated with a spectrum of clinically heterogeneous phenotypes with biallelic perturbation. Despite its clinical relevance, the mechanistic underpinnings of these variants remain elusive, underscoring the need for extensive case series and functional investigations. In this study, we conducted a systematic review of cases in the literature through two electronic databases following the PRISMA guidelines. We selected nine studies, including 18 patients, with homozygous or compound heterozygous variants in MPDZ and added five patients from four unrelated families with novel MPDZ variants. To evaluate the role of Mpdz on hearing, we analyzed available auditory electrophysiology data from a knockout murine model (Mpdzem1(IMPC)J/em1(IMPC)J) generated by the International Mouse Phenotyping Consortium. Using exome and genome sequencing, we identified three families with compound heterozygous variants, and one family with a homozygous frameshift variant. MPDZ-related disease is clinically heterogenous with hydrocephaly, vision impairment, hearing impairment and cardiovascular disease occurring most frequently. Additionally, we describe two unrelated patients with spasticity, expanding the phenotypic spectrum. Our murine analysis of the Mpdzem1(IMPC)J/em1(IMPC)J allele showed severe hearing impairment. Overall, we expand understanding of MPDZ-related phenotypes and highlight hearing impairment and spasticity among the heterogeneous phenotypes.

Evaluating the association between MPDZ-NF1B rs1324183 and keratoconus in an independent northwestern Chinese population.

BACKGROUND: Keratoconus (KC) is a complex, non-inflammatory corneal degenerative disease. Although numerous studies have analyzed the correlation of SNP rs1324183, which located in MPDZ-NF1B gene, and KC in different populations, only few findings were repeated. In this study, to evaluate the association between rs1324183 and KC in a new independent Chinese population, we performed a replication study of the significantly associated rs1324183. METHODS: In total of 114 unrelated KC patients and 88 unrelated controls were recruited from Ningxia, China. We detected the genotypes and alleles of rs1324183 using PCR technology and Sanger sequencing and also analyzed the association between this locus and KC, its clinical parameters by statistical methods. RESULTS: The frequency of genotype AA (11, 9.6%) and genotypes containing allele A (47, 41.2%) of rs1324183 in KC were both higher than those of the control group. And genotype AA of rs1324183 conferred a higher risk of KC (OR > 1). Moreover, corneal parameter Belin/Ambrósio enhanced ectasia display final D value (BAD-D) had significant correlation (p = 0.002) with AA genotype of rs1324183 in KC. CONCLUSIONS: Our replication study indicates that the results of rs1324183 associated with KC in our population is robust and further better illustrates the significance of BAD-D as a diagnostic indicator for KC. rs1324183 should be considered as the first genetic mark of KC risk in its future diagnosis.

Rare single nucleotide variants in COL5A1 promoter do not play a major role in keratoconus susceptibility associated with rs1536482.

BACKGROUND: Keratoconus is a chronic degenerative disorder of the cornea characterized by thinning and cone-shaped protrusions. Although genetic factors play a key role in keratoconus development, the etiology is still under investigation. The occurrence of single-nucleotide polymorphisms (SNPs) associated with keratoconus in Russian patients is poorly studied. The purpose of this study was to validate whether three reported keratoconus-associated SNPs (rs1536482 near the COL5A1 gene, rs2721051 near the FOXO1 gene, rs1324183 near the MPDZ gene) are also actual for a Russian cohort of patients. Additionally, we investigated the COL5A1 promoter sequence for single-nucleotide variants (SNVs) in a subgroup of keratoconus patients with at least one rs1536482 minor allele (rs1536482+) to assess the role of these SNVs in keratoconus susceptibility associated with rs1536482. METHODS: This case-control study included 150 keratoconus patients and two control groups (main and additional, 205 and 474 participants, respectively). We performed PCR targeting regions flanking SNVs and the COL5A1 promoter, followed by Sanger sequencing of amplicons. The additional control group was genotyped using an SNP array. RESULTS: The minor allele frequency was significantly different between the keratoconus and control cohorts (main and combined) for rs1536482, rs2721051, and rs1324183 (p-value < 0.05). The rare variants rs1043208782 and rs569248712 were found in the COL5A1 promoter in two out of 94 rs1536482+ keratoconus patients. CONCLUSION: rs1536482, rs2721051, and rs1324183 were associated with keratoconus in a Russian cohort. SNVs in the COL5A1 promoter do not play a major role in keratoconus susceptibility associated with rs1536482.

A genome-wide significant association on chromosome 2 for footrot resistance/susceptibility in Swiss White Alpine sheep.

Footrot is one of the most important causes of lameness in global sheep populations and is characterized by a bacterial infection of the interdigital skin. As a multifactorial disease, its clinical representation depends not only on pathogen factors and environmental components but also on the individual resistance/susceptibility of the host. A genetic component has been shown in previous studies; however, so far no causative genetic variant influencing the risk of developing footrot has been identified. In this study, we genotyped 373 Swiss White Alpine sheep, using the ovine high-density 600k SNP chip, in order to run a DNA-based comparison of individuals with known clinical footrot status. We performed a case-control genome-wide association study, which revealed a genome-wide significant association for SNP rs418747104 on ovine chromosome 2 at 81.2 Mb. The three best associated SNP markers were located at the MPDZ gene, which codes for the multiple PDZ domain crumbs cell polarity complex component protein, also known as multi-PDZ domain protein 1 (MUPP1). This protein is possibly involved in maintaining the barrier function and integrity of tight junctions. Therefore, we speculate that individuals carrying MPDZ variants may differ in their footrot resistance/susceptibility due to modified horn and interdigital skin integrity. In conclusion, our study reveals that MPDZ might represent a functional candidate gene, and further research is needed to explore its role in footrot affected sheep.

Novel MPDZ/MUPP1 transgenic and knockdown models confirm Mpdz's role in ethanol withdrawal and support its role in voluntary ethanol consumption.

Association studies implicate multiple PDZ domain protein (MPDZ/MUPP1) sequence and/or expression in risk for alcoholism in humans and ethanol withdrawal (EW) in mice, but confirmation has been hindered by the dearth of targeted genetic models. We report the creation of transgenic (MPDZ-TG) and knockout heterozygote (Mpdz(+/-) ) mice, with increased (2.9-fold) and decreased (53%) target expression, respectively. Both models differ in EW compared with wild-type littermates (P ≤ 0.03), providing compelling evidence for an inverse relationship between Mpdz expression and EW severity. Additionally, ethanol consumption is reduced up to 18% (P = 0.006) in Mpdz(+/-) , providing the first evidence implicating Mpdz in ethanol self-administration.

MPDZ is associated with immune infiltration and regulates migration and invasion by switching YAP1 phosphorylation in colorectal cancer.

BACKGROUND: Multiple PDZ Domain Crumbs Cell Polarity Complex Component (MPDZ) is involved in a few human cancers. However, the features and potential mechanisms of MPDZ in progression of colorectal cancer (CRC) remains unknown. METHODS: The prognostic role of MPDZ in CRC was determined by Kaplan-Meier and univariate regression analysis. Enrichment analysis was performed to characterize crucial pathways of MPDZ. Immune infiltration and immunotherapeutic outcome were further evaluated. CCK8, EDU, transwell, and wound healing assay were used to assess the influence of MPDZ on pernicious performance of CRC cells. CD8+ T cells and CRC cells were co-cultured to explore the effect of MPDZ on the tumor microenvironment. qRT-PCR, western blot, immunoprecipitation (IP), and methylated RNA immunoprecipitation (me-RIP) were implemented in seeking for the potential mechanisms of MPDZ in CRC. RESULTS: CRC patients with elevated MPDZ expression suffered from significantly worse prognosis. Enrichment analysis revealed that MPDZ involved in pathways related to metastasis and cell cycle in CRC. In addition, MPDZ expression were related to several immunoinhibitors and had the ability to predict immunotherapy response. Finally, in vitro assays demonstrated that MPDZ knockdown inhibited migration, invasion and immune evasion of CRC cells. Mechanistically, MPDZ knockdown enhanced YAP1 phosphorylation by increased LATS1 expression. Moreover, m6A-MPDZ mRNA may be recognized and degraded by m6A recognition protein YTHDF2. CONCLUSIONS: MPDZ was critical for CRC development and could be a promising candidate for the treatment of CRC patients.

Retinal manifestations in autosomal recessive MPDZ maculopathy: report of two cases and literature review.

BACKGROUND: To present the retinal and systemic findings in two siblings with compound heterozygous MPDZ variants that were found to have different chorioretinal manifestations. Materials and Methods: Two sibling patients underwent comprehensive ophthalmic examination, including ophthalmoscopy, fundus photography, optical coherence tomography (OCT), and genetic testing by whole exome sequencing. RESULTS: A 4-year-old male presented with intermittent exotropia and decreased vision in both eyes. Ophthalmologic examination was notable for macular colobomas and far temporal chorioretinal atrophy in both eyes. OCT of the macula in both eyes demonstrated a caldera with severe retinal and choroidal thinning. Fluorescein angiography of the central macula showed hypofluorescence with persistence of deep choroidal vessels. An ocular gene panel was nondiagnostic, but subsequent whole-exome sequencing noted compound heterozygous, likely pathogenic MPDZ variants (c.3100C>T p.(Arg1034*) from father and c.747 + 2T>G p.(?) from mother). His older brother, a 9-year-old male, had a history of macrocephaly but had not undergone further workup. On exam, he had a visual acuity of 20/25 in the right eye and 20/40 in the left eye and was found to have subtle changes in the foveal reflex of both eyes. OCT revealed thinning of the outer nuclear layer (ONL) temporal to the fovea bilaterally. Sanger sequencing revealed he was positive for the same two MPDZ variants. CONCLUSIONS: MPDZ variants have been described in cases of congenital hydrocephalus with varying ophthalmologic manifestations. We present a case series describing retinal phenotypes associated with MPDZ variants in a single family through multimodal imaging.

Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla.

Congenital hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid in the ventricular system. Four major genes are currently known to be causally involved in hydrocephalus, either isolated or as a common clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Here, we report 3 cases from 2 families with congenital hydrocephalus due to bi-allelic variations in CRB2, a gene previously reported to cause nephrotic syndrome, variably associated with hydrocephalus. While 2 cases presented with renal cysts, one case presented with isolated hydrocephalus. Neurohistopathological analysis allowed us to demonstrate that, contrary to what was previously proposed, the pathological mechanisms underlying hydrocephalus secondary to CRB2 variations are not due to stenosis but to atresia of both Sylvius Aqueduct and central medullar canal. While CRB2 has been largely shown crucial for apico-basal polarity, immunolabelling experiments in our fetal cases showed normal localization and level of PAR complex components (PKCι and PKCζ) as well as of tight (ZO-1) and adherens (ß-catenin and N-Cadherin) junction molecules indicating a priori normal apicobasal polarity and cell-cell adhesion of the ventricular epithelium suggesting another pathological mechanism. Interestingly, atresia but not stenosis of Sylvius aqueduct was also described in cases with variations in MPDZ and CCDC88C encoding proteins previously linked functionally to the Crumbs (CRB) polarity complex, and all 3 being more recently involved in apical constriction, a process crucial for the formation of the central medullar canal. Overall, our findings argue for a common mechanism of CRB2, MPDZ and CCDC88C variations that might lead to abnormal apical constriction of the ventricular cells of the neural tube that will form the ependymal cells lining the definitive central canal of the medulla. Our study thus highlights that hydrocephalus related to CRB2, MPDZ and CCDC88C constitutes a separate pathogenic group of congenital non-communicating hydrocephalus with atresia of both Sylvius aqueduct and central canal of the medulla.

Novel Compound Heterozygous Variations in MPDZ Gene Caused Isolated Bilateral Macular Coloboma in a Chinese Family.

Macular coloboma (MC) is a rare congenital retinochoroidal defect characterized by lesions of different sizes in the macular region. The pathological mechanism underlying congenital MC is unknown. Novel compound heterozygous variations, c.4301delA (p.Asp1434fs*3) and c.5255C>G (p.Ser1752Ter), in the multiple PDZ domain (MPDZ) proteins were identified via whole-exome analysis on the proband with isolated bilateral macular coloboma in a Chinese family. Segregation analysis revealed that each of the unaffected parents was heterozygous for one of the two variants. The results of the in silico and bioinformatics analysis were aligned with the experimental data. The knockdown of MPDZ in zebrafish caused a decrease in the ellipsoid zone, a destruction of the outer limiting membrane, and the subsequent RPE degeneration. Overall, the loss of MPDZ in zebrafish contributed to retinal development failure. These results indicate that MPDZ plays an essential role in the occurrence and maintenance of the macula, and the novel compound heterozygous variations were responsible for an autosomal recessive macular deficiency in this Chinese family.

Genomic analysis of paired IDHwt glioblastomas reveals recurrent alterations of MPDZ at relapse after radiotherapy and chemotherapy.

PURPOSE: We aimed to identify genomic drivers of glioblastoma inevitable recurrence. METHODS: Ten pairs of initial and recurrent frozen IDHwt glioblastoma samples were screened by CGH Array. Next Generation Sequencing (NGS) was then performed on an enriched cohort of 19 pairs. MPDZ alterations were analyzed using TCGA dataset. RESULTS: Nineteen IDHwt glioblastoma patients were included. Median age was 54.5 y/o (37.2-72.8). Using CGH array, unsupervised analysis aggregated the cohort by paired initial and recurrent tumors. Only 44% of CGH Array alterations were conserved at recurrence (amplifications: 55%; deletions: 30%). Two regions (including FPR1, 2 and 3) were lost at relapse: 19q13.33 and 19q13.41. MPDZ and 25 other genes were altered in ≥20% of recurrent tumors. NGS analysis of 29 candidate genes revealed 4 genes with pathogenic mutations: (FPR2, REL, TYRP1 and MPDZ). MPDZ (Multiple PDZ Domain Crumbs Cell Polarity Complex Component) was altered by two pathogenic mutations occurring at relapse. Using TCGA dataset we observed that a lower MPDZ mRNA expression was associated with IDHwt (p < 0.001) and grade IV (p < 0.001) gliomas. Finally, a low mRNA MPDZ expression was significantly correlated to poor overall survival in both IDHwt and IDH mutated gliomas, reinforcing the potential pejorative impact of MPDZ loss. CONCLUSION: Our results suggest that MPDZ is more frequently altered at relapse after radio-chemotherapy in glioblastoma IDHwt patients, suggesting that MPDZ impairment could contribute to the systematic resistance of these tumors opening new therapeutic perspectives.

Identification and Computational Analysis of Rare Variants of Known Hearing Loss Genes Present in Five Deaf Members of a Pakistani Kindred.

Hearing loss (HL) is the most common neurosensory defect in humans that affects the normal communication. Disease is clinically and genetically heterogeneous, rendering challenges for the molecular diagnosis of affected subjects. This study highlights the phenotypic and genetic complexity of inherited HL in a large consanguineous Pakistan kindred. Audiological evaluation of all affected individuals revealed varying degree of mild to profound sensorineural HL. Whole exome (WES) of four family members followed by Sanger sequencing revealed candidate disease-associated variants in five known deafness genes: GJB2 (c.231G>A; p.(Trp77 *)), SLC26A4 (c.1337A>G; p.(Gln446Arg)), CDH23 (c.2789C>T; p.(Pro930Leu)), KCNQ4 (c.1672G>A; p.(Val558Met)) and MPDZ (c.4124T>C; p.(Val1375Ala)). All identified variants replaced evolutionary conserved residues, were either absent or had low frequencies in the control databases. Our in silico and 3-Dimensional (3D) protein topology analyses support the damaging impact of identified variants on the encoded proteins. However, except for the previously established "pathogenic" and "likely pathogenic" categories for the c.231G>A (p.(Trp77 *)) allele of GJB2 and c.1377A>G (p.(Gln446Arg)) of SLC26A4, respectively, all the remaining identified variants were classified as "uncertain significance" based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant pathogenicity guidelines. Our study highlights the complexity of genetic traits in consanguineous families, and the need of combining the functional studies even with the comprehensive profiling of multiple family members to improve the genetic diagnosis in complex inbred families.

Linking fold, function and phylogeny: a comparative genomics view on protein (domain) evolution.

Domains are the building blocks of all globular proteins and present one of the most useful levels at which protein function can be understood. Through recombination and duplication of a limited set of domains, proteomes evolved and the collection of protein superfamilies in an organism formed. As such, the presence of a shared domain can be regarded as an indicator of similar function and evolutionary history, but it does not necessarily imply it since convergent evolution may give rise to similar gene functions as well as architectures.Through the wealth of sequences and annotation data brought about by genomics, evolutionary links can be sought for via homology relationships and comparative genomics, structural modeling and phylogenetics. The goal hereby is not only to predict the function of newly discovered proteins, but also to spell out their pathway of evolution and, possibly, identify their most likely origin. This can ultimately help to understand protein function and functional relationships of protein families. Additionally, through comparison with transcriptional data, evolutionary data can be linked to gene (and genome) activity and thus allow for the identification of common principles behind fast evolving proteins and relatively stable ones.In this review, we describe the basic principles of studying protein (domain) evolution and illustrate recent developments in molecular evolution and give valuable new insights in the field of comparative genomics. As an example, we include here molecular models of the multiple PDZ domain protein MUPP-1 and present a simple comparative genomic view on its structural course of evolution.

Asymmetric distribution of CRUMBS polarity complex proteins from compacted 8-cell to blastocyst stage during mouse preimplantation development.

During mouse preimplantation development, blastomeres are equipotent until polarity establishment at compacted 8-cell stage. The intrinsic nature of polarity is the asymmetric distribution of polarity proteins between inside and outside blastomeres along the direction of apical-basal axis. This study investigated the early developmental temporal and spatial expression of the main CRUMBS polarity complex proteins in the mouse preimplantation embryo. We observed that Crb3, Pals1, Patj and Mpdz are transcribed in the mouse preimplantation embryo. However, the asymmetric distribution of these polarity proteins is not established until the compacted 8-cell stage. From compaction and thereafter, CRB3 and PALS1 are progressively enriched in the apical membrane, while PATJ and MPDZ are discretely localized at both tight junctions and the apical membrane adjacent to tight junctions. These temporal and spatial distribution patterns suggest that CRUMBS polarity complex might be involved in the cell polarity establishment in the early mouse embryo and reinforce the viewpoint that developmentally spatial asymmetries are first set up at the compaction stage. The present study provides a foundation for further investigation on the functions of CRUMBS polarity complex in trophectoderm specification and blastocyst morphogenesis.

MPDZ promotes DLL4-induced Notch signaling during angiogenesis.

Angiogenesis is coordinated by VEGF and Notch signaling. DLL4-induced Notch signaling inhibits tip cell formation and vessel branching. To ensure proper Notch signaling, receptors and ligands are clustered at adherens junctions. However, little is known about factors that control Notch activity by influencing the cellular localization of Notch ligands. Here, we show that the multiple PDZ domain protein (MPDZ) enhances Notch signaling activity. MPDZ physically interacts with the intracellular carboxyterminus of DLL1 and DLL4 and enables their interaction with the adherens junction protein Nectin-2. Inactivation of the MPDZ gene leads to impaired Notch signaling activity and increased blood vessel sprouting in cellular models and the embryonic mouse hindbrain. Tumor angiogenesis was enhanced upon endothelial-specific inactivation of MPDZ leading to an excessively branched and poorly functional vessel network resulting in tumor hypoxia. As such, we identified MPDZ as a novel modulator of Notch signaling by controlling ligand recruitment to adherens junctions.

Copy number variations and expression of MPDZ are prognostic biomarkers for clear cell renal cell carcinoma.

The vital copy number variation (CNV) plays a crucial role in clear cell renal cell carcinoma (ccRCC). MPDZ inhibit cell polarity associate with osmotic pressure response and cancer-related biological processes. In order to clarify the role of the CNV of MPDZ in the progression of ccRCC, we analyzed the CNV and expression of MPDZ and prognosis in ccRCC patients from The Cancer Genome Atlas data portal. Notably, we found that the deletion of MPDZ was the common CNV, which was present in 28.65% of ccRCC patients. With the development of tumors, the percentage of MPDZ deletion increased significantly (19.38% in stage I; 20.00% in stage II; 40.94% in stage III; and 45.00% in stage IV). The deletion of MPDZ significantly increased ccRCC risk (P=0.0025). Low MPDZ expression associated with its deletion was significantly associated with adverse outcomes in ccRCC patients (P=0.0342). Furthermore, immunohistochemical analysis by tissue microarray showed that MPDZ was expressed at lower levels in tumor tissues compared with adjacent tissues (P<0.01). Kaplan-Meier survival curves showed that ccRCC patients with low MPDZ expression had significantly shorter survival than those with high MPDZ expression (P=0.002). These results indicated that low MPDZ expression associated with CNV is a potential biomarker for the prognosis of ccRCC patients.

Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene.

Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.

Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal.

Association studies implicate the multiple PDZ domain protein (MUPP1/MPDZ) gene in risk for alcoholism in humans and alcohol withdrawal in mice. Although manipulation of the Mpdz gene by homologous recombination and bacterial artificial chromosome transgenesis has suggested that its expression affects alcohol withdrawal risk, the potential confounding effects of linked genes and developmental compensation currently limit interpretation. Here, using RNA interference (RNAi), we directly test the impact of Mpdz expression on alcohol withdrawal severity and provide brain regional mechanistic information. Lentiviral-mediated delivery of Mpdz short hairpin RNA (shRNA) to the caudolateral substantia nigra pars reticulata (clSNr) significantly reduces Mpdz expression and exacerbates alcohol withdrawal convulsions compared with control mice that delivered a scrambled shRNA. Neither baseline nor pentylenetetrazol-enhanced convulsions differed between Mpdz shRNA and control animals, indicating Mpdz expression in the clSNr does not generally affect seizure susceptibility. To our knowledge, these represent the first in vivo Mpdz RNAi analyses, and provide the first direct evidence that Mpdz expression impacts behavior. Our results confirm that Mpdz is a quantitative trait gene for alcohol withdrawal and demonstrate that its expression in the clSNr is crucially involved in risk for alcohol withdrawal.

Identification of new binding partners of the chemosensory signaling protein Gγ13 expressed in taste and olfactory sensory cells.

Tastant detection in the oral cavity involves selective receptors localized at the apical extremity of a subset of specialized taste bud cells called taste receptor cells (TRCs). The identification of the genes coding for the taste receptors involved in this process have greatly improved our understanding of the molecular mechanisms underlying detection. However, how these receptors signal in TRCs, and whether the components of the signaling cascades interact with each other or are organized in complexes is mostly unexplored. Here we report on the identification of three new binding partners for the mouse G protein gamma 13 subunit (Gγ13), a component of the bitter taste receptors signaling cascade. For two of these Gγ13 associated proteins, namely GOPC and MPDZ, we describe the expression in taste bud cells for the first time. Furthermore, we demonstrate by means of a yeast two-hybrid interaction assay that the C terminal PDZ binding motif of Gγ13 interacts with selected PDZ domains in these proteins. In the case of the PDZ domain-containing protein zona occludens-1 (ZO-1), a major component of the tight junction defining the boundary between the apical and baso-lateral region of TRCs, we identified the first PDZ domain as the site of strong interaction with Gγ13. This association was further confirmed by co-immunoprecipitation experiments in HEK 293 cells. In addition, we present immunohistological data supporting partial co-localization of GOPC, MPDZ, or ZO-1, and Gγ13 in taste buds cells. Finally, we extend this observation to olfactory sensory neurons (OSNs), another type of chemosensory cells known to express both ZO-1 and Gγ13. Taken together our results implicate these new interaction partners in the sub-cellular distribution of Gγ13 in olfactory and gustatory primary sensory cells.