Disease relevance of Pcdh1

• The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene [1].
• Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F [2].
• Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype [3].
• The emergence of protocadherin-PC expression during the acquisition of apoptosis-resistance by prostate cancer cells [4].

High impact information on Pcdh1

• Here we report that the gene that harbours the av mutation encodes a novel protocadherin [1].
• This is the first evidence for the requirement of a protocadherin for normal function of the mammalian inner ear [1].
• Recent progress in genome sequencing has enabled a refined phylogenetic analysis of protocadherins and led to the discovery of three large protocadherin clusters on human chromosome 5/mouse chromosome 18 [5].
• Despite the extensive analyses of the genomic structure of both human and mouse Pcdh gene clusters, the definitive molecular mechanisms that control Pcdh gene expression are still unknown [6].
• Molecular mechanisms governing Pcdh-gamma gene expression: evidence for a multiple promoter and cis-alternative splicing model [6].

Chemical compound and disease context of Pcdh1

• Protocadherin-PC promotes androgen-independent prostate cancer cell growth [7].

Biological context of Pcdh1

• Mouse Pcdh1 and Pcdh2 were mapped to a small segment of chromosome 18, suggesting that various protocadherins form a gene cluster at this region [8].
• To study the diversity of the protocadherin family, the cDNA clones for a novel protocadherin were isolated by screening rat brain cDNA libraries with a cDNA fragment obtained by PCR, and some of the properties were then characterized [9].
• Multiple alpha and gamma Pcdh mRNAs are expressed in distinct patterns in the nervous system and are generated by alternative pre-mRNA splicing between different "variable" exons and three "constant" exons within each cluster [10].
• The murine genome contains approximately 70 protocadherin (Pcdh) genes [11].
• Previous work using tools of Drosophila genetics suggested that protocadherin fat serves in a pathway necessary for determining cell polarity in the plane of a tissue [12].

Anatomical context of Pcdh1

• Pcdh genes are abundantly expressed in the central nervous system [6].
• The genomic architecture of protocadherin (Pcdh) gene clusters is remarkably similar to that of the immunoglobulin and T cell receptor gene clusters, and can potentially provide significant molecular diversity [6].
• Interpretation of this phenotype was complicated, however, by the fact that Pcdh-gamma loss also led to apoptosis of many spinal interneurons [13].
• Consistent with this idea, mice lacking all 22 genes of the Pcdh-gamma cluster have decreased numbers of spinal cord synapses and are nearly immobile [13].
• PCNS: a novel protocadherin required for cranial neural crest migration and somite morphogenesis in Xenopus [14].

Associations of Pcdh1 with chemical compounds

• However, Reelin has also been proposed to signal through integrin and protocadherin [15].

Regulatory relationships of Pcdh1

• Interaction with protocadherin-gamma regulates the cell surface expression of protocadherin-alpha [16].

Other interactions of Pcdh1

• We named this protocad herin-3 (Pcdh3) since this is the third protocadherin of which the entire coding sequence has been determined [9].
• This subfamily can be further subdivided into two subgroups, named delta1-protocadherins (comprising protocadherin-1, -7, -9, and -11 or X/Y) and delta2-protocadherins (comprising protocadherin-8, -10, -17, -18, and -19) [17].
• In contrast, the expression of EphA4 (Epha4), lunatic fringe or protocadherin, thought to be involved in segment border formation, was fairly normal in hypomorphic mutant embryos [18].
• We show that these mutants, spin cycle and crash, carry independent missense mutations within the coding region of Celsr1, encoding a large protocadherin molecule [1] [19].
• By linkage analyses, the mutant phenotype was mapped near marker D10Mit186 and the protocadherin gene Pcdh15 [20].

Analytical, diagnostic and therapeutic context of Pcdh1

• By fluorescence in situ hybridization, we placed the human homolog of the mouse protocadherin Pcdh15 in the linkage interval defined by the USH1F locus [21].
• Sequence analysis and expression mapping of the rat clustered protocadherin gene repertoires [22].

References