Long isoforms of the COPD risk gene FAM13A orchestrate human lung epithelial development

Impaired lung development and lung function can lead to the development of chronic obstructive pulmonary disease (COPD). Genome wide association studies (GWAS) have identified associations between variants in the gene FAM13A with both lung function and COPD. Of the major FAM13A isoforms expressed in humans, only the shorter isoforms are expressed in mice. This species difference has hindered investigations into whether full-length, human-specific isoforms contribute to human lung development, a question that remains unstudied to date. To functionally address this question, we disrupted the long isoform of FAM13A in human induced pluripotent stem cells (iPSCs). Specific loss of this isoform prevented the emergence in culture of mature airway or alveolar epithelial lineages in directed differentiation protocols. We demonstrate that the FAM13A long isoform is critical to patterning NKX2-1 + lung progenitor cells through dysregulating Wnt/β-catenin signaling during early stages of development in vitro. These findings provide the first evidence that the COPD risk gene FAM13A may be vital in the developing human lung epithelium.