Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, 52621, Israel,
J Clin Immunol. 2014 Jan;34(1):76-83. doi: 10.1007/s10875-013-9957-3. Epub 2013 Nov 7.
Chromosomal instability syndromes include a group of rare diseases characterized by defective DNA-damage-response and increased risk of chromosomal breakage. Patients display defects in the recognition and/or repair of DNA damage, with a subsequent high rate of malignancies and abnormal gene rearrangements. Other clinical manifestations, such as immunodeficiency, neurodevelopmental delay and skeletal abnormalities, are present in some of these syndromes. We studied a patient with profound T-lymphocyte defect, neurodevelopmental delay, facial dysmorphism, nephrotic syndrome and spondyloepiphyseal bone dysplasia typical of SIOD.
Karyotype and chromosome fragility assays on patients' peripheral blood mononuclear cells showed an abnormal rate of spontaneous breaks. Cell cycle analysis of patient's fibroblasts following replication stress induced by hydroxyhurea revealed a delay in their release from S-phase to G2. When using higher concentrations of hydroxyhurea no patient fibroblast colonies could survive, compared with control fibroblasts. Whole-exome sequencing revealed novel compound heterozygote mutations in SMARCAL1 gene, resulting in putative frame shifts of encoded SMARCAL1 from each allele and no detected protein in patient's cells. The patient's youngest brother was found to have similar manifestations of SIOD but of less severity, including short stature, facial dysmorphism and typical osseous dysplasia, but no clinical findings suggestive of immunodeficiency and no chromosomal fragility. Similar to his sister, the brother carries both bi-allelic mutations in SMARCAL1 gene.
We present here the first evidence of intrinsic chromosomal instability in a severe SMARCAL1-deficient patient with a clinical picture of SIOD. Our results are consistent with the recently outlined role of SMARCAL1 protein in DNA damage response.
染色体不稳定综合征包括一组罕见疾病，其特征为 DNA 损伤反应缺陷和染色体断裂风险增加。患者表现出 DNA 损伤的识别和/或修复缺陷，随后恶性肿瘤和异常基因重排的发生率很高。这些综合征中的一些还存在其他临床表现，如免疫缺陷、神经发育迟缓、骨骼异常等。我们研究了一名患者，其表现为严重的 T 淋巴细胞缺陷、神经发育迟缓、面部畸形、肾病综合征和典型 SIOD 的脊椎骨骺骨软骨发育不良。
患者外周血单个核细胞的核型和染色体脆性分析显示自发断裂的异常率。羟基脲诱导复制应激后，患者成纤维细胞的细胞周期分析显示其从 S 期到 G2 期的释放延迟。当使用更高浓度的羟基脲时，与对照成纤维细胞相比，没有患者成纤维细胞集落能够存活。全外显子组测序显示 SMARCAL1 基因的新型复合杂合突变，导致每个等位基因编码的 SMARCAL1 产生推定的移码，并在患者细胞中未检测到蛋白。发现患者的弟弟也有类似的 SIOD 表现，但病情较轻，包括身材矮小、面部畸形和典型的骨骼发育不良，但没有提示免疫缺陷的临床发现，也没有染色体脆性。与他的姐姐一样，弟弟携带 SMARCAL1 基因的两个等位基因均发生突变。
我们在此首次报道了一名严重 SMARCAL1 缺陷患者存在内在染色体不稳定的证据，其临床表现为 SIOD。我们的结果与最近提出的 SMARCAL1 蛋白在 DNA 损伤反应中的作用一致。
