A constitutive BCL2 down-regulation aggravates the phenotype of PKD1-mutant induced polycystic kidney disease.

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Date publication

septembre 2017


Human molecular genetics


Membres identifiés du Cancéropôle Est :
Pr CALLIER Patrick, Pr FAIVRE Laurence, Pr LOFFROY Romaric

Tous les auteurs :
Duplomb L, Droin N, Bouchot O, Thauvin CR, Bruel AL, Thevenon J, Callier P, Meurice G, Pata-Merci N, Loffroy R, Vandroux D, Da Costa R, Carmignac V, Solary E, Faivre L


The main identified function of BCL2 protein is to prevent cell death by apoptosis. Mice knock-out for Bcl2 demonstrate growth retardation, severe polycystic kidney disease (PKD), gray hair and lymphopenia, and die prematurely after birth. Here, we report a 40-year-old male referred to for abdominal and thoracic aortic dissection with associated aortic root aneurysm, PKD, lymphocytopenia with a history of T cell lymphoblastic lymphoma, white hair since the age of 20, and learning difficulties. PKD, which was also detected in the father and sister, was related to an inherited PKD1 mutation. The combination of PKD with gray hair and lymphocytopenia was also reminiscent of Bcl2-/- mouse phenotype. BCL2 gene transcript and protein level were observed to be dramatically decreased in patient peripheral blood T-cells and in his aorta vascular wall cells, which was not detected in parents and sister T-cells, suggesting an autosomal recessive inheritance. Accordingly, spontaneous apoptosis of patient T-cells was increased and could be rescued through stimulation with an anti-CD3 antibody. Direct sequencing of BCL2 gene exons, promoter and 3'UTR region as well as BCL2 mRNA sequencing failed in identifying any pathogenic variant. Array-CGH was also normal and whole exome sequencing of the patient, parents and sister DNA did not detect any significant variant in genes encoding Bcl2-interacting proteins. miRNA array identified an up-regulation of miR-181a, which is a known regulator of BCL2 expression. Altogether, miR-181a-mediated decrease in BCL2 gene expression could be a modifying factor that aggravates the phenotype of a PKD1 constitutive variant.

Mots clés

Adult, Animals, Apoptosis, genetics, Down-Regulation, Exons, Genetic Predisposition to Disease, Humans, Male, Mice, Mice, Knockout, MicroRNAs, metabolism, Pedigree, Phenotype, Polycystic Kidney, Autosomal Dominant, genetics, Proto-Oncogene Proteins c-bcl-2, genetics, TRPP Cation Channels, genetics, Up-Regulation


Hum. Mol. Genet.. 2017 Sep;: