Biallelic loss-of-function PTPN6 variants lead to inflammatory lung disease and hemolytic anemia.
Severe inflammatory lung disease, including acute respiratory distress syndrome (ARDS), is life-threatening with diverse causes and few targeted therapies. Inborn errors of immunity (IEIs) underlie a subset of cases. We describe a novel IEI caused by biallelic loss-of-function variants in PTPN6, encoding the immunoregulatory phosphatase SHP1. Seven children from five families developed early-onset anemia and severe inflammatory lung disease, at times presenting as ARDS. The causative variants were shown to destabilize SHP1 and abolish its phosphatase activity. These findings expand the genetic landscape of inflammatory lung disease and suggest SHP1 activation as a potential therapeutic strategy for immune-mediated pulmonary pathology.
Authors
Moussavi-Harami Moussavi-Harami, Zinter Zinter, Motta Motta, Pannone Pannone, Calligari Calligari, Mignini Mignini, Slavotinek Slavotinek, Martin Martin, Sanchez Sanchez, Sanchez Sanchez, Ragab Ragab, Abram Abram, Broly Broly, Abi Ayad Abi Ayad, Serradj Serradj, Boursier Boursier, Bertoli-Avella Bertoli-Avella, Sadagopan Sadagopan, Parvaneh Parvaneh, Sedighzadeh Sedighzadeh, Mirzaei Mirzaei, Shahrooei Shahrooei, Hsu Hsu, Holland Holland, Bocchinfuso Bocchinfuso, Stella Stella, Martinelli Martinelli, Reversade Reversade, Tartaglia Tartaglia, Lowell Lowell, Looney Looney, Chan Chan
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