CFTR acts as a potential therapeutic target for attention deficit-hyperactivity disorder.

The prevalence of attention deficit-hyperactivity disorder (ADHD) symptoms among individuals with cystic fibrosis (CF) is significantly elevated compared to the general population. Given that the cystic fibrosis transmembrane conductance regulator (CFTR) is the causative gene for cystic fibrosis, this raises the possibility of CFTR playing a crucial role in ADHD. In our study, three heterozygous missense variants (p.E217G, p.F316L, and p.T1220I) were detected in the CFTR gene, which co-segregate with ADHD in two consanguineous families, impacting a total of six family members. Through the utilization of a zebrafish model, it was observed that the cftr knockout line exhibited behaviors akin to hyperactivity, impulsivity, and attention deficits, mirroring the symptoms seen in human ADHD patients. Single-cell RNA sequencing performed on 7 dpf larvae revealed clusters of neuron cells that exhibited sensitivity to cftr, particularly noting a reduction in the number of dopaminergic neuron cells within the cftr mutant fish. Additionally, bulk RNA sequencing and proteomic analysis conducted during the early gastrulation stage demonstrated abnormal expression levels of nervous system genes. Notably, we attempted to employ CFTR modulators Lumacaftor (VX-809) and Ivacaftor (VX-770) to ameliorate the ADHD zebrafish model (generated via per1b mutant), and it was found that enhanced CFTR activity could mitigate ADHD-like behaviors. In summary, our findings shed light on the potential involvement of CFTR in the pathogenesis of ADHD and pave the way for exploring novel diagnostic approaches and therapeutic strategies for ADHD by targeting CFTR.