iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

Abstract

PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and craniofacial abnormalities resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). PACS1 is known to play roles in both the endosomal pathway and nucleus, but little is known about how this variant affects the developing nervous system and patients have few therapeutic options. Here, we used stem cell-derived forebrain organoids to show that PACS1(+/R203W) cells share convergent molecular features of autism spectrum disorder (ASD) through a gain-of-function mechanism. These features include an aberrant propensity towards GABAergic differentiation, increased inhibitory synaptic density, and impaired expression of an ASD-specific gene network enriched at synapses. This work is the first to investigate the impact of the p.R203W variant on the developing brain and suggests a therapy that either clears p.R203W PACS1 or targets convergent pathological mechanisms of ASD could be beneficial for patients.

Molecular Basis of the Schuurs–Hoeijmakers Syndrome: What We Know about the Gene and the PACS-1 Protein and Novel Therapeutic Approaches

“…Nowadays, there are a few studies regarding the relationship between PACS-1 function and the PACS1 -NDD phenotype. It is proposed that the most frequent PACS-1 variant, p.R203W, causes a gain-of-function (GOF) or a dominant negative mechanism [ 1 , 48 ]. However, the truncation of the protein (del ex12-24) with a loss-of-function has been described in two patients with a mild and not characteristic PACS1 -NDD clinic [ 6 ].…”

“…Gene expression pattern experiments showed differences between the PACS1 (+/R203W) and the control model, but not between the PACS1 (-/-) and the control, supporting the idea that this specific mutation confers a GOF and a toxic effect on the protein. Genes directly related to the autism spectrum disorder (ASD) and to the development of GABAergic synapses are upregulated in the disease model [ 48 ]. These results support the previous findings that about 40% of the PACS1 -NDD patients have been formally diagnosed with autism [ 49 ].…”

“…In recent years, more targeted therapy approaches are being developed for some rare diseases. In this sense, the PACS1 -NDD is a good candidate [ 50 ] because most of the patients carry the same mutation, and a gain-of-function or a dominant negative mechanism has been proposed [ 1 , 3 , 48 ]. However, the highest expression level of PACS-1 during fetal brain development could limit the effectiveness of the treatment [ 31 , 32 ].…”