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.

RBL2/p130 是视网膜母细胞瘤蛋白家族的成员，是细胞分裂的关键调节因子，可传播不可逆的衰老。RBL2/p130 也参与神经元分化和存活，在某些小鼠品系中消除 RBL2 会导致胚胎致死，并伴有异常的中枢神经系统 (CNS) 表型。关于 RBL2/p130 在 DNA 甲基转移酶 (DNMT) 转录调控以及端粒长度控制中的作用存在相互矛盾的报道。在这里，我们描述了携带双等位基因RBL2的三名患者的表型-截断变体。所有患者均出现婴儿肌张力减退、严重发育迟缓和小头畸形。携带者或患者未报告恶性肿瘤。先前对小鼠和人类培养细胞进行的研究表明，RBL2 缺失与 DNA 甲基化和端粒长度失调有关。在这里，我们调查了缺乏 RBL2 的患者细胞是否显示相关异常。对原发性患者成纤维细胞的研究未检测到 DNMT 表达的异常。此外，全基因组 DNA 的甲基化水平，特别是着丝粒周围重复序列和亚端粒区域的甲基化水平不受干扰。RBL2-null 成纤维细胞没有证据表明端粒重组导致异常伸长。最后，在连续培养RBL2突变的成纤维细胞。因此，这项研究解决了关于 RBL2 在 DNA 甲基化和端粒长度调节中潜在的非冗余作用的不确定性，并表明RBL2中功能变体的丧失导致人类严重的常染色体隐性神经发育障碍。