Samra Nadra, Jansen Nicolette S, Morani Ilham, Kakun Reli Rachel, Zaid Rinat, Paperna Tamar, Garcia-Dominguez Mario, Viner Yuri, Frankenthal Hilel, Shinwell Eric S, Portnov Igor, Bakry Doua, Shalata Adel, Shapira Rootman Mika, Kidron Dvora, Claessens Laura A, Wevers Ron A, Mandel Hanna, Vertegaal Alfred C O, Weiss Karin
Department of Genetics, Ziv Medical Center, Safed, Israel.
Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
J Med Genet. 2023 Nov;60(11):1133-1141. doi: 10.1136/jmg-2023-109267. Epub 2023 Jul 17.
SUMOylation involves the attachment of small ubiquitin-like modifier (SUMO) proteins to specific lysine residues on thousands of substrates with target-specific effects on protein function. Sentrin-specific proteases (SENPs) are proteins involved in the maturation and deconjugation of SUMO. Specifically, SENP7 is responsible for processing polySUMO chains on targeted substrates including the heterochromatin protein 1α (HP1α).
We performed exome sequencing and segregation studies in a family with several infants presenting with an unidentified syndrome. RNA and protein expression studies were performed in fibroblasts available from one subject.
We identified a kindred with four affected subjects presenting with a spectrum of findings including congenital arthrogryposis, no achievement of developmental milestones, early respiratory failure, neutropenia and recurrent infections. All died within four months after birth. Exome sequencing identified a homozygous stop gain variant in c.1474C>T; p.(Gln492*) as the probable aetiology. The proband's fibroblasts demonstrated decreased mRNA expression. Protein expression studies showed significant protein dysregulation in total cell lysates and in the chromatin fraction. We found that HP1α levels as well as different histones and H3K9me3 were reduced in patient fibroblasts. These results support previous studies showing interaction between SENP7 and HP1α, and suggest loss of SENP7 leads to reduced heterochromatin condensation and subsequent aberrant gene expression.
Our results suggest a critical role for SENP7 in nervous system development, haematopoiesis and immune function in humans.
小泛素样修饰物（SUMO）化涉及将SUMO蛋白连接到数千种底物上的特定赖氨酸残基，对蛋白质功能产生靶标特异性影响。Sentrin特异性蛋白酶（SENP）参与SUMO的成熟和去共轭过程。具体而言，SENP7负责处理包括异染色质蛋白1α（HP1α）在内的靶标底物上的多聚SUMO链。
我们对一个有几名婴儿患有不明综合征的家庭进行了外显子组测序和分离研究。对一名受试者的成纤维细胞进行了RNA和蛋白质表达研究。
我们鉴定出一个家系，其中有四名受影响的受试者，表现出一系列症状，包括先天性关节挛缩、未达到发育里程碑、早期呼吸衰竭、中性粒细胞减少和反复感染。所有患者均在出生后四个月内死亡。外显子组测序确定c.1474C>T；p.(Gln492*)处的纯合终止密码子获得性变异可能是病因。先证者的成纤维细胞显示mRNA表达降低。蛋白质表达研究表明，总细胞裂解物和染色质组分中存在明显的蛋白质失调。我们发现患者成纤维细胞中HP1α水平以及不同的组蛋白和H3K9me3均降低。这些结果支持了先前显示SENP7与HP1α相互作用的研究，并表明SENP7的缺失导致异染色质浓缩减少以及随后的异常基因表达。
我们的结果表明SENP7在人类神经系统发育、造血和免疫功能中起关键作用。
