Abstract
RBL2/p130, a member of the retinoblastoma family of proteins, is a key regulator of cell division and propagates irreversible senescence. RBL2/p130 is also involved in neuronal differentiation and survival, and eliminating Rbl2 in certain mouse strains leads to embryonic lethality accompanied by an abnormal central nervous system (CNS) phenotype. Conflicting reports exist regarding a role of RBL2/p130 in transcriptional regulation of DNA methyltransferases (DNMTs), as well as the control of telomere length. Here we describe the phenotype of three patients carrying bi-allelic RBL2-truncating variants. All presented with infantile hypotonia, severe developmental delay and microcephaly. Malignancies were not reported in carriers or patients. Previous studies carried out on mice and human cultured cells, associated RBL2 loss to DNA methylation and telomere length dysregulation. Here, we investigated whether patient cells lacking RBL2 display related abnormalities. The study of primary patient fibroblasts did not detect abnormalities in expression of DNMTs. Furthermore, methylation levels of whole genome DNA, and specifically of pericentromeric repeats and subtelomeric regions, were unperturbed. RBL2-null fibroblasts show no evidence for abnormal elongation by telomeric recombination. Finally, gradual telomere shortening, and normal onset of senescence were observed following continuous culturing of RBL2-mutated fibroblasts. Thus, this study resolves uncertainties regarding a potential non-redundant role for RBL2 in DNA methylation and telomere length regulation, and indicates that loss of function variants in RBL2 cause a severe autosomal recessive neurodevelopmental disorder in humans.
Original language | English |
---|---|
Pages (from-to) | 1101-1112 |
Number of pages | 12 |
Journal | Journal of Human Genetics |
Volume | 66 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2021 |
Bibliographical note
Publisher Copyright:© 2021, The Author(s), under exclusive licence to The Japan Society of Human Genetics.
Funding
Acknowledgements We are grateful for the families support and willingness to participate in this research study. We thank Tamar Paperna and Daniel Kornitzer for comments on the manuscript. ST is grateful to The Edmond de Rothschild Foundation (IL) for funding her PhD scholarship. This work was supported by the Israel Science Foundation [grant number 1362/17 to SS]. KW is supported by the Clinical Research Institute at Rambam.
Funders | Funder number |
---|---|
Edmond de Rothschild Foundation | |
Israel Science Foundation | 1362/17 |