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

Nadra Samra, Nicolette S. Jansen, Ilham Morani, Reli Rachel Kakun, Rinat Zaid, Tamar Paperna, Mario Garcia-Dominguez, Yuri Viner, Hilel Frankenthal, Eric S. Shinwell, Igor Portnov, Doua Bakry, Adel Shalata, Mika Shapira Rootman, Dvora Kidron, Laura A. Claessens, Ron A. Wevers, Hanna Mandel, Alfred C.O. Vertegaal, Karin Weiss

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1 Scopus citations


Background 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). Methods 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. Results 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 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. Conclusion Our results suggest a critical role for SENP7 in nervous system development, haematopoiesis and immune function in humans.

Original languageEnglish
Pages (from-to)1133-1141
Number of pages9
JournalJournal of Medical Genetics
Issue number11
Early online date17 Jul 2023
StatePublished - 1 Nov 2023

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Publisher Copyright:
© 2023 Author(s). Published by BMJ.


  • allergy and immunology
  • nervous system diseases
  • proteomics


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