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Original research
Exome sequencing links the SUMO protease SENP7 with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia
  1. Nadra Samra1,2,
  2. Nicolette S Jansen3,
  3. Ilham Morani1,
  4. Reli Rachel Kakun4,
  5. Rinat Zaid5,
  6. Tamar Paperna5,
  7. Mario Garcia-Dominguez6,
  8. Yuri Viner2,7,
  9. Hilel Frankenthal2,7,
  10. Eric S Shinwell2,8,
  11. Igor Portnov2,8,
  12. Doua Bakry2,9,
  13. Adel Shalata10,
  14. Mika Shapira Rootman11,
  15. Dvora Kidron12,
  16. Laura A Claessens3,
  17. Ron A Wevers13,
  18. Hanna Mandel14,
  19. Alfred C O Vertegaal3,
  20. Karin Weiss5,15
  1. 1 Department of Genetics, Ziv Medical Center, Safed, Israel
  2. 2 Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
  3. 3 Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
  4. 4 The Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel
  5. 5 The Genetics Institute, Rambam Health Care Campus, Haifa, Israel
  6. 6 Andalusian Centre for Molecular Biology and Regenerative Medicine-CABIMER, CSIC-Universidad Pablo de Olavide, Sevilla, Spain
  7. 7 Pediatric Intensive Care Unit, Ziv Medical Center, Safed, Israel
  8. 8 Department of Neonatology, Ziv Medical Center, Safed, Israel
  9. 9 Department of Pediatric Hematology, Ziv Medical Center, Safed, Israel
  10. 10 Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, Haifa, Israel
  11. 11 Department of Radiology, Rambam Health Care Campus, Haifa, Israel
  12. 12 Department of Pathology, Meir Medical Center, Kfar Saba, Israel
  13. 13 Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
  14. 14 Metabolic unit, Ziv Medical Center, Safed, Israel
  15. 15 The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
  1. Correspondence to Dr Karin Weiss, Genetics, Rambam Health Care Campus, Haifa, Israel; k_weiss{at}; Prof Alfred C O Vertegaal; a.c.o.vertegaal{at}


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.

  • nervous system diseases
  • allergy and immunology
  • proteomics

Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. Additional raw data are available on request.

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Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. Additional raw data are available on request.

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  • NS and NSJ contributed equally.

  • Contributors NS, HM: conceptualisation, data curation, writing draft. NSJ, ACOV: conceptualisation, data curation, analysis, methodology, writing draft. IM, RRK, RZ, LAC, DK: data curation, analysis, methodology. MG-D, RAW: draft editing. YV, HF, ESS, IP, DB, AS, MSR: data curation. TP: data curation, analysis, methodology, draft editing. KW: guarantor, conceptualisation, writing draft.

  • Funding ACOV is supported by the Dutch Research Council (NWO, 724.016.003). KW is supported by the Clinical Research Institute at Rambam.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.