Laboratory of Genome Dynamics in the Immune System, Laboratoire labellisé Ligue Naionale contre le Cancer, INSERM UMR 1163, Université de Paris, Imagine Institute, Paris, France.
U1068 INSERM, Unité Mixte de Recherche (UMR) 7258 (CNRS), Equipe Labellisée Ligue Nationale Contre le Cancer, Marseille Cancer Research Center (CRCM), Institut Paoli-Calmettes, Aix Marseille University, Marseille, France.
Blood. 2022 Apr 21;139(16):2427-2440. doi: 10.1182/blood.2021010791.
Inherited bone marrow failure syndromes (IBMFSs) are a group of disorders typified by impaired production of 1 or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant, Høyeraal-Hreidarsson (HH) syndrome, are rare IBMFSs characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. We identified biallelic variants in the gene encoding the 5'-to-3' DNA exonuclease Apollo/SNM1B in 3 unrelated patients presenting with a DC/HH phenotype consisting of early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation. All 3 patients carry a homozygous or compound heterozygous (in combination with a null allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients' cells showed signs of telomere fragility that were not associated with global reduction of telomere length. Unlike patients' cells, human Apollo KO HT1080 cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS that combines clinical hallmarks of DC/HH with normal telomere length.
遗传性骨髓衰竭综合征（IBMFSs）是一组以一种或多种血细胞生成受损为特征的疾病。端粒生物学疾病先天性角化不良（DC）及其严重变异型 Hoyeraal-Hreidarsson（HH）综合征是罕见的 IBMFSs，其特征为骨髓衰竭、发育缺陷和各种与临界端粒缩短相关的过早衰老并发症。我们在 3 名表现为 DC/HH 表型的无关联患者中发现了编码 5'-3'DNA 外切酶 Apollo/SNM1B 的基因的双等位基因变异，该表型由早期发生的低细胞性骨髓衰竭、B 和 NK 淋巴细胞减少、发育异常、小头症和/或宫内生长迟缓组成。所有 3 名患者均携带纯合或复合杂合（与无效等位基因结合）错义变异，影响位于 Apollo 催化结构域的相同残基 L142（L142F 或 L142S）。来自患者的 Apollo 缺陷细胞表现出自发性染色体不稳定和 DNA 修复受损，CRISPR/Cas9 介导的基因校正可对其进行补充。此外，患者的细胞表现出端粒脆弱的迹象，但与端粒长度的整体减少无关。与患者的细胞不同，人 Apollo KO HT1080 细胞系表现出强烈的端粒功能障碍，伴有过度的端粒缩短，表明 L142S 和 L142F Apollo 变体是低功能的。总之，这些发现将人类 Apollo 定义为基因组守护者，并确定双等位基因 Apollo 变体是一种尚未被认识到的严重 IBMFS 的遗传原因，该综合征结合了 DC/HH 的临床特征和正常的端粒长度。
