2. Academic Validation
  3. RBL2 bi-allelic truncating variants cause severe motor and cognitive impairment without evidence for abnormalities in DNA methylation or telomeric function

RBL2 bi-allelic truncating variants cause severe motor and cognitive impairment without evidence for abnormalities in DNA methylation or telomeric function

  • J Hum Genet. 2021 Nov;66(11):1101-1112. doi: 10.1038/s10038-021-00931-z.
Nadra Samra 1 2,  Shir Toubiana 3,  Hilde Yttervik 4,  Aya Tzur-Gilat 3,  Ilham Morani 1,  Chen Itzkovich 5,  Liran Giladi 3,  Kamal Abu Jabal 6,  John Z Cao 7,  Lucy A Godley 7,  Adi Mory 8 9,  Hagit Baris Feldman 8 10 9,  Kristian Tveten 11,  Sara Selig # 12 13,  Karin Weiss # 8 10
Affiliations

Affiliations

  • 1 Genetic Unit, Ziv Medical Center, Tzfat, Israel.
  • 2 Faculty of Medicine, Bar Ilan University, Tzfat, Israel.
  • 3 Department of Genetics and Developmental Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
  • 4 Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
  • 5 The Clinical Research Institute at Rambam Health Care Campus, Haifa, Israel.
  • 6 Ziv Medical Center, Tzfat, Israel.
  • 7 Section of Hematology Oncology, Departments of Medicine and Human Genetics, The University of Chicago, Chicago, IL, USA.
  • 8 The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
  • 9 The Genetics Institute, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 10 The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
  • 11 Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway.
  • 12 Department of Genetics and Developmental Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. [email protected].
  • 13 Laboratory of Molecular Medicine, Rambam Health Care Campus, Haifa, Israel. [email protected].
  • # Contributed equally.
PMID: 33980986 DOI: 10.1038/s10038-021-00931-z
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.

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