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RBL2 bi-allelic truncating variants cause severe motor and cognitive impairment without evidence for abnormalities in DNA methylation or telomeric function.
- Source :
-
Journal of human genetics [J Hum Genet] 2021 Nov; Vol. 66 (11), pp. 1101-1112. Date of Electronic Publication: 2021 May 13. - Publication Year :
- 2021
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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.<br /> (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)
- Subjects :
- Adolescent
Adult
Alleles
Animals
Child
Cognitive Dysfunction complications
Cognitive Dysfunction physiopathology
Developmental Disabilities complications
Developmental Disabilities genetics
Developmental Disabilities physiopathology
Female
Fibroblasts metabolism
Genetic Predisposition to Disease
Humans
Male
Methyltransferases genetics
Mice
Microcephaly complications
Microcephaly genetics
Microcephaly physiopathology
Motor Activity physiology
Muscle Hypotonia complications
Muscle Hypotonia genetics
Muscle Hypotonia physiopathology
Telomere genetics
Exome Sequencing
Cognitive Dysfunction genetics
DNA Methylation genetics
Retinoblastoma-Like Protein p130 genetics
Telomere Shortening genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1435-232X
- Volume :
- 66
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 33980986
- Full Text :
- https://doi.org/10.1038/s10038-021-00931-z