RB1CC1 duplication and aberrant overexpression in a patient with schizophrenia: further phenotype delineation and proposal of a pathogenetic mechanism.
RB1CC1
autophagy
copy number variations (CNVs)
schizophrenia (SCZ)
suicidality
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
revised:
20
11
2020
received:
20
07
2020
accepted:
05
11
2020
pubmed:
20
12
2020
medline:
3
8
2021
entrez:
19
12
2020
Statut:
ppublish
Résumé
Copy number variants in coding and noncoding genomic regions have been implicated as risk factor for schizophrenia (SCZ). Rare duplications of the RB1CC1 gene were found enriched in SCZ patients. Considering that the effect of such duplications on RB1CC1 expression has never been evaluated and partial gene duplications of RB1CC1 have also been reported in SCZ patients, it is unclear whether the pathogenesis is mediated by haploinsufficiency rather than genuine overexpression of the gene. We studied a patient with schizophrenia, suicidality, and obesity, who carried a de novo RB1CC1 complete duplication, as assessed by high-resolution array-CGH. Molecular breakpoint cloning allowed to identify nonhomologous end joining (NHEJ) as driving mechanism in this rearrangement. On the contrary, trio-based whole-exome sequencing excluded other potential causative variants related to the phenotype. Functional assays showed significant overexpression of RB1CC1 in the peripheral blood lymphocytes of the proband compared to control subjects, suggesting overdosage as leading mechanism in SCZ pathophysiology. We hypothesized a pathogenetic model that might explain the correlation between RB1CC1 overexpression and schizophrenia by altering different cell signaling pathways, including autophagy, a promising therapeutic target for schizophrenic patients.
Sections du résumé
BACKGROUND
Copy number variants in coding and noncoding genomic regions have been implicated as risk factor for schizophrenia (SCZ). Rare duplications of the RB1CC1 gene were found enriched in SCZ patients. Considering that the effect of such duplications on RB1CC1 expression has never been evaluated and partial gene duplications of RB1CC1 have also been reported in SCZ patients, it is unclear whether the pathogenesis is mediated by haploinsufficiency rather than genuine overexpression of the gene.
METHODS AND RESULTS
We studied a patient with schizophrenia, suicidality, and obesity, who carried a de novo RB1CC1 complete duplication, as assessed by high-resolution array-CGH. Molecular breakpoint cloning allowed to identify nonhomologous end joining (NHEJ) as driving mechanism in this rearrangement. On the contrary, trio-based whole-exome sequencing excluded other potential causative variants related to the phenotype. Functional assays showed significant overexpression of RB1CC1 in the peripheral blood lymphocytes of the proband compared to control subjects, suggesting overdosage as leading mechanism in SCZ pathophysiology.
CONCLUSION
We hypothesized a pathogenetic model that might explain the correlation between RB1CC1 overexpression and schizophrenia by altering different cell signaling pathways, including autophagy, a promising therapeutic target for schizophrenic patients.
Identifiants
pubmed: 33340270
doi: 10.1002/mgg3.1561
pmc: PMC7963413
doi:
Substances chimiques
Autophagy-Related Proteins
0
RB1CC1 protein, human
0
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1561Informations de copyright
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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