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Heterozygous single nucleotide variants (SNVs) or copy\u2010number variant (CNV) deletions involving dosage\u2010sensitive <jats:italic>TBX4<\/jats:italic> have been associated with pulmonary arterial hypertension (PAH), ischiocoxopodopatellar syndrome with or without PAH, and lethal lung developmental disorders (LLDDs), including acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD), and other unspecified primary pulmonary hypoplasias. Loss\u2010 and gain\u2010of\u2010function variants have been proposed to cause pediatric PAH and LLDDs, and adult forms of PAH, respectively. Of more than 50 missense SNVs scattered across the entire <jats:italic>TBX4<\/jats:italic>, only three have been reported in patients with LLDDs, all mapping to the T\u2010box domain. Here, we report a recurrence of a pathogenic substitution Glu86Lys identified in an unrelated patient with AcDys. <jats:italic>In silico<\/jats:italic> predictions of the conformational changes of TBX4 resulting from this and another substitution, Glu86Gln, suggest the loss of most intermolecular hydrogen bonds involving residue 86, including those with Tyr230 that directly interact with DNA. Functional assays on the <jats:italic>TBX4<\/jats:italic> variants in fetal lung fibroblasts confirmed their deleterious character. We propose that Glu86 is critically involved in maintaining TBX4 structure and function essential for airway branching during early stages of human lung development. Substitutions of this residue may act in a dominant negative manner, leading to AcDys and CAD.<\/jats:p>","DOI":"10.1002\/ajmg.a.63936","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T08:00:23Z","timestamp":1731916823000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Glu86 Residue in <scp>TBX4<\/scp> Proves Critical for Human Lung Development"],"prefix":"10.1002","volume":"197","author":[{"given":"Przemyslaw","family":"Szafranski","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Gambin","sequence":"additional","affiliation":[{"name":"Institute of Computer Science Warsaw University of Technology  Warsaw 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