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CELSR2, encoding a planar cell polarity protein, is a putative gene in Joubert syndrome with cortical heterotopia, microophthalmia, and growth hormone deficiency.

ABSTRACT: Joubert syndrome is a ciliopathy characterized by a specific constellation of central nervous system malformations that result in the pathognomonic "molar tooth sign" on imaging. More than 27 genes are associated with Joubert syndrome, but some patients do not have mutations in any of these genes. Celsr1, Celsr2, and Celsr3 are the mammalian orthologues of the drosophila planar cell polarity protein, flamingo; they play important roles in neural development, including axon guidance, neuronal migration, and cilium polarity. Here, we report bi-allelic mutations in CELSR2 in a Joubert patient with cortical heterotopia, microophthalmia, and growth hormone deficiency. © 2017 Wiley Periodicals, Inc.

SUBMITTER: Vilboux T

PROVIDER: S-EPMC7299154 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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CELSR2, encoding a planar cell polarity protein, is a putative gene in Joubert syndrome with cortical heterotopia, microophthalmia, and growth hormone deficiency.

Vilboux Thierry T Malicdan May Christine V MC Roney Joseph C JC Cullinane Andrew R AR Stephen Joshi J Yildirimli Deniz D Bryant Joy J Fischer Roxanne R Vemulapalli Meghana M Mullikin James C JC Steinbach Peter J PJ Gahl William A WA Gunay-Aygun Meral M

American journal of medical genetics. Part A 20170104 3

Joubert syndrome is a ciliopathy characterized by a specific constellation of central nervous system malformations that result in the pathognomonic "molar tooth sign" on imaging. More than 27 genes are associated with Joubert syndrome, but some patients do not have mutations in any of these genes. Celsr1, Celsr2, and Celsr3 are the mammalian orthologues of the drosophila planar cell polarity protein, flamingo; they play important roles in neural development, including axon guidance, neuronal mig ...[more]

PMID: 28052552

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Project description:BackgroundTreatment and outcomes of breast cancer, one of the most prevalent female cancers, have improved in recent decades. However, metastatic breast cancer remains incurable in most cases, and new therapies are needed to ameliorate prognosis. Planar cell polarity (PCP) is a characteristic of epithelial cells that form layers and is integral to the communication of these cells with neighboring cells. Dysfunction of PCP is observed in cancers and may confer a targetable vulnerability.MethodsThe breast cancer cohorts from The Cancer Genome Atlas (TCGA) and the METABRIC study were interrogated for molecular alterations in genes of the PCP pathway. The groups with the most prevalent alterations were characterized, and survival was compared with counterparts not possessing PCP alterations. Breast cancer cell lines with PCP alterations from the Cancer Cell Line Encyclopedia (CCLE) were interrogated for sensitivity to drugs affecting PCP.ResultsAmong genes of the PCP pathway, VANGL2, NOS1AP and SCRIB display amplifications in a sizable minority of breast cancers. Concomitant up-regulation at the mRNA level can be observed mostly in basal cancers, but it does not correlate well with the amplification status of the genes, as it can also be observed in non-amplified cases. In an exploration of cell line models, two of the four breast cancer cell line models with amplifications in VANGL2, NOS1AP and SCRIB display sensitivity to drugs inhibiting acyl-transferase porcupine interfering with the WNT pathway. This sensitivity suggests a possible therapeutic role of these inhibitors in cancers bearing the amplifications.ConclusionMolecular alterations in PCP genes can be observed in breast cancers with a predilection for the basal sub-type. An imperfect correlation of copy number alterations with mRNA expression suggests that post-translational modifications are important in PCP regulation. Inhibitors of acyl-transferase porcupine may be rational candidates for combination therapy development in PCP-altered breast cancers.

Dataset Information

CELSR2, encoding a planar cell polarity protein, is a putative gene in Joubert syndrome with cortical heterotopia, microophthalmia, and growth hormone deficiency.

Publications

CELSR2, encoding a planar cell polarity protein, is a putative gene in Joubert syndrome with cortical heterotopia, microophthalmia, and growth hormone deficiency.

Similar Datasets

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