Exome sequencing links the SUMO protease SENP7 with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia

• Published in: Journal of medical genetics Vol. 60; no. 11; pp. 1133 - 1141
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.11.2023; BMJ Publishing Group LTD
• Subjects: allergy and immunology; Arthrogryposis; Chromatin; Disease; Enzymes; Fibroblasts; Gene expression; Genetic testing; Genomes; Hemopoiesis; Heterochromatin; Histones; Immune response; Infections; Lysates; Membranes; Nervous system; nervous system diseases; Neutropenia; Novel disease loci; Plasmids; Proteins; Proteomics; Respiratory failure; Software; SUMO protein; Ubiquitin; United States > US; California; proteomics; nervous system diseases; allergy and immunology
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmg-2023-109267

BackgroundSUMOylation 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).MethodsWe 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.ResultsWe 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 SENP7 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.ConclusionOur results suggest a critical role for SENP7 in nervous system development, haematopoiesis and immune function in humans.