Dataset Information

Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome

ABSTRACT: Enlarged vestibular aqueducts (EVA) is one of the most commonly identified inner ear malformations in hearing loss patients including Pendred syndrome. While biallelic mutations of the SLC26A4 gene, encoding pendrin, causes non-syndromic hearing loss with EVA or Pendred syndrome, a considerable number of patients appear to carry mono-allelic mutation. This suggests faulty pendrin regulatory machinery results in hearing loss. Here we identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4. EphA2 forms a protein complex with pendrin controlling pendrin localization, which is disrupted in some pathogenic forms of pendrin. Moreover, point mutations leading to amino acid substitution in the EPHA2 gene are identified from patients bearing mono-allelic mutation of SLC26A4. Ephrin-B2 binds to EphA2 triggering internalization with pendrin inducing EphA2 autophosphorylation weakly. The identified EphA2 mutants attenuate ephrin-B2- but not ephrin-A1-induced EphA2 internalization with pendrin. Our results uncover an unexpected role of the Eph/ephrin system in epithelial function.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Scientific Service Group Biomolecular Mass Spectrometry

LAB HEAD: Masanori Nakayama

PROVIDER: PXD017011 | Pride | 2020-04-22

REPOSITORIES: Pride

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Publications

Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome.

Li Mengnan M Nishio Shin-Ya SY Naruse Chie C Riddell Meghan M Sapski Sabrina S Katsuno Tatsuya T Hikita Takao T Mizapourshafiyi Fatemeh F Smith Fiona M FM Cooper Leanne T LT Lee Min Goo MG Asano Masahide M Boettger Thomas T Krueger Marcus M Wietelmann Astrid A Graumann Johannes J Day Bryan W BW Boyd Andrew W AW Offermanns Stefan S Kitajiri Shin-Ichiro SI Usami Shin-Ichi SI Nakayama Masanori M

Nature communications 20200312 1

Enlarged vestibular aqueduct (EVA) is one of the most commonly identified inner ear malformations in hearing loss patients including Pendred syndrome. While biallelic mutations of the SLC26A4 gene, encoding pendrin, causes non-syndromic hearing loss with EVA or Pendred syndrome, a considerable number of patients appear to carry mono-allelic mutation. This suggests faulty pendrin regulatory machinery results in hearing loss. Here we identify EPHA2 as another causative gene of Pendred syndrome wit ...[more]

PMID: 32165640

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Project description:Objective We have previously shown that expression of the CEACAM1 long isoform (CC1-L) in metastatic colorectal cancer (CRC) cells results in significant inhibition of liver metastasis via Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Yet, despite recent advances in identifying molecules involved in the CC1-L inhibition of metastasis, much remains to be elucidated regarding the molecular mechanisms orchestrating this pathway. Design We performed an untargeted transcript profiling and a phosphokinase screen between CC1-L-expressing and non-expressing (CT) CRC cells. Identified targets were validated in vitro and in vivo for their involvement in signaling and invasion or metastasis. We validated our conclusions in CRC patient cohorts for time to metastasis development and long-term survival. Results Untargeted transcript profiling revealed high Decorin (Dcn) expression in CC1-L-expressing cells versus CT cells. Decorin was detected at the peri-endothelial layers of large blood vessels and in liver stellate cells. In metastatic lesions, it was expressed in pericyte-like cells covering capillary endothelium. Phosphokinase differential screening revealed reduced Ephrin type-A receptor 2 (EphA2) expression and activity in CC1-L- versus CT-expressing cells. Treatment of CT cells with recombinant Dcn led to decreased migration and invasion and decreased EphA2-mediated Erk and Akt signaling. CRC patients exhibiting high CC1 and DCN expression, in combination with low EPHA2 expression, benefit from longer 10-year survival than those with high EPHA2 expression. Conclusion CC1-L expression in poorly differentiated CRC inhibits liver metastasis through increased Decorin expression and EphA2-mediated signaling. Quadriplicate samples of each mouse colon cancer cell lines (control cells versus those expressing either short or long isoform of CEACAM1) have been used for RNA extraction

Dataset Information

Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome

Publications

Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome.

Similar Datasets

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