Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

The mechanisms behind the loss of epithelial barrier function leading to alveolar flooding in acute lung injury (ALI) are incompletely understood. We hypothesized that the tyrosine kinase receptor human epidermal growth factor receptor-2 (HER2) would be activated in an inflammatory setting and participate in ALI. Interleukin-1␤ (IL-1␤) exposure resulted in HER2 activation in human epithelial cells and markedly increased conductance across a monolayer of airway epithelial cells. Upon HER2 blockade, conductance changes were significantly decreased. Mechanistic studies revealed that HER2 trans-activation by IL-1␤ required a disintegrin and metalloprotease 17 (ADAM17)-dependent shedding of the ligand neuregulin-1 (NRG-1). In murine models of ALI, NRG-1-HER2 signaling was activated, and ADAM17 blockade resulted in decreased NRG-1 shedding, HER2 activation, and lung injury in vivo. Finally, NRG-1 was detectable and elevated in pulmonary edema fluid from patients with ALI. These results suggest that the ADAM17-NRG-1-HER2 axis modulates the alveolar epithelial barrier and contributes to the pathophysiology of ALI. Acute lung injury (ALI)3 is a severe clinical disorder with an annual incidence of ϳ200,000 and a mortality of 40% in the United States (1). Most commonly seen in the setting of sepsis (2-4), ALI is marked by disruption of the alveolar barrier, leukocyte activation, release of inflammatory cytokines, and hypercoagulability. The net effect is an increase in alveolar epithelial permeability, resulting in alveolar flooding with proteinrich edema and life-threatening hypoxemia (5). An intact epithelial barrier is essential to maintaining normal pulmonary fluid balance. Indeed, damage to the endothelium alone is insufficient to cause pulmonary edema, whereas epithelial injury results in severe lung injury (6 -8). The epithelium provides a greater resistance to proteins and fluid than the capillary endothelium and is responsible for the active ion transport-dependent removal of edema fluid from the distal air spaces of the lung (9 -11).The tyrosine kinase receptor human epidermal growth factor receptor-2 (HER2) is expressed by pulmonary bronchial epithelial cells and is involved in multiple physiologic processes, including cell proliferation and wound repair. The HER receptor family consists of four type 1, membrane-bound tyrosine kinase receptors: HER1 or epidermal growth factor receptor (EGFR), HER2, HER3, and HER4 (12). HER2 has no known ligand and requires partnering with another HER family member for activation. HER2 and 3 are highly expressed in pulmonary bronchial epithelial cells (compared with HER1 and 4) (13). HER3 is the receptor for the ligand neuregulin-1 (NRG-1), but HER3 has no intrinsic signaling properties (14). Upon NRG-1 binding, HER3 heterodimerizes with HER2, resulting in activation of the HER2 tyrosine kinase domain, HER2 autophosphorylation, and initiation of downstream intracellular signaling cascades (13). NRG-1 is expressed in bronchial epithelial cells (13,15,16) and is shed from the cell ...

Inhibiting TNF-α or src kinases may be a therapeutic option to normalize barrier integrity and cytokine release in airway diseases associated with barrier dysfunction.