Friday, May 16, 2025
5/16/2025
Neurodevelopmental mechanisms in 17q12 CNV disorders and autism - PROJECT SUMMARY Copy number variants (CNVs) are contiguous gene deletions or duplications that confer susceptibility to neuro- psychiatric and neurodevelopmental disorders (NDDs). Thereby, CNVs offer a powerful opportunity to investi- gate multigenic mechanisms in complex brain disease. Recent studies demonstrate that the 17q12 Deletion (17qDel) is among the strongest CNV risk factors for autism; however, the mechanisms of circuit dysgenesis caused by 17q12Dels remain poorly understood. The objective of this research is to define defective neurode- velopmental mechanisms caused by 17q12 CNVs, particularly 17q12Dels, which represent a high-penetrant, high-confidence risk factor for autism and related neurodevelopmental disorders (NDDs). To meet this objec- tive, we have generated unique experimental resources, including: a 17q12Del mouse; and human 17q12 CNV induced pluripotent stem cells (iPSCs) (with robust controls), from patients with 17q12Dels, as well as from pa- tients with reciprocal 17q12 duplications. Our central hypothesis is that the combinatorial haploinsufficiency of the genes within the interval, including the transcription factor Lhx1, a known regulator of Wnt signaling, dis- rupts multiple steps in brain and circuit development. Notably, we have discovered that 17q12Del mice exhibit a spectrum of anterior brain and craniofacial abnormalities. These phenotypes vary depending on the mouse genetic background, and are akin to, but milder than, the Lhx1-null mouse. The 17q12Del on the inbred C57BL/6N background displays greater phenotypic severity, including neonatal lethality, compared to 17q12Del mice on the outbred CD-1 background, that survive into adulthood with milder cortical and hippo- campal abnormalities. We will pursue the following Aims: 1) Define defective transcriptional mechanisms and molecular pathways in embryonic brain development in 17q12Del mice; 2) Define defective molecular path- ways and rescue strategies in patient-derived 17q12 CNV neurons; and 3) Define postnatal neurodevelopmen- tal and behavioral abnormalities in 17q12Del mice on diverse background genetics using MRI morphometry, molecular and behavioral studies. This research will have a sustained impact on the field given the high level of significance and innovation: 1) 17q12Dels represent an understudied, high-confidence autism locus; 2) the study of Wnt signaling will permit convergence of the 17q12Del mutation with other high-confidence autism genes; 3) we are testing proof-of-concept Wnt-related therapeutics; 4) methodologically, study of an autism- associated mutation on diverse, mouse genetic backgrounds provides an important, experimental paradigm for investigating phenotypic heterogeneity; and 5) we use an integrated translational approach, that involves a multidisciplinary team coordinating cross-species experiments, including in vivo rodent and in vitro human iPSC models, with clinical studies in patients. This research will permit bench-to-bedside and broadly-signifi- cant discoveries related to the diversity of phenotypes and treatment responses in neuropsychiatric disorders.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).