25 March 2024

Researchers have identified a new genetic mutation involved in severe combined immune deficiency (SCID).

It is the first time a mutation in the proteasome has been linked to SCID, the researchers say.

The discovery has been made jointly by researchers from Nijmegen, Holland, and Newcastle, UK. It emerged from the study of a baby treated successfully with a stem cell transplant in 2005.

Four more cases were found worldwide, including three in Newcastle. The children had been diagnosed with the SCID-Omenn syndrome and a fourth case then emerged in Newcastle, all linked to the PSMB10 gene.

Researcher Professor Alexander Hoischen, from Radboud University Medical Centre, said: “We already know mutations in other proteins of the proteasome lead to autoinflammatory diseases, such as periodic fevers.

“It is possible that mutations in PSMB10 lead to improper cutting of proteins from bacteria and other pathogens. This cutting is important because the immune system recognizes, picks up and disposes of invaders based on well-cut, characteristic protein fragments, from well-made molecular photographs you might say. Without a good picture, there’s no detection.

“Possibly the proteasome also plays a role in cutting pieces of protein used by the immune system itself. But exactly how it does so requires further research. For now, the importance of getting this news out to patients as soon as possible was key.”

Paediatrician Dr Stefanie Henriet said: “This discovery has direct implications for SCID newborn screening, for counselling on stem cell transplants and treatment of severe inflammatory complications.”

Professor Sophie Hambleton, from the University of Newcastle, added: “It shows that sporadic, dominant mutations cause severe combined immunodeficiency more often than was thought. This is important for affected babies and their families. Now that we can base treatment choices on early genetic diagnosis of this condition, we hope that outcomes will improve.”


van der Made CI, Kersten S, Chorin O, Engelhardt KR, Ramakrishnan G, Griffin H, Schim van der Loeff I, Venselaar H, Rothschild AR, Segev M, Schuurs-Hoeijmakers JHM, Mantere T, Essers R, Esteki MZ, Avital AL, Loo PS, Simons A, Pfundt R, Warris A, Seyger MM, van de Veerdonk FL, Netea MG, Slatter MA, Flood T, Gennery AR, Simon AJ, Lev A, Frizinsky S, Barel O, van der Burg M, Somech R, Hambleton S, Henriet SSV, Hoischen A. (2024) “Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome.” American Journal of Human Genetics, doi: 10.1016/j.ajhg.2024.02.013

Link: https://www.cell.com/ajhg/fulltext/S0002-9297(24)00045-4

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