PACS2

The PACS2 gene encodes for the protein phosphofurin acidic cluster sorting protein 2. The PACS2 protein serves as a multifunctional sorting protein that shuttles cargo between the endomembrane system. It also serves as a mitochondrial-associated membrane (MAM) protein that resides at mitochondrial-ER contact sites and acts as a regulator of calcium transfer, autophagosome formation, autophagy, and apoptosis.

Individuals with PACS2 syndrome share a de novo heterozygous missense variant (c.625 G>A) that causes an amino acid substitution from glutamic acid to lysine at position 209 (p.E209K). There is one reported case of an individual with PACS2 syndrome with p.E211K.

The PACS2 Research Foundation reports there are around 40-50 cases of individuals with PACS2 syndrome worldwide.

Individuals with PACS2 syndrome share a general phenotype consisting of early onset epilepsy, cerebellar dysgenesis, intellectual disability, and facial dysmorphisms.

Research in the Guemez-Gamboa Lab at Northwestern University strives to understand the pathogenic mechanisms of PACS2 syndrome. Their work uses iPSC-derived neuronal models like neural progenitor cells and forebrain organoids to investigate how the E209K variant affects mitochondrial function, protein interactions, and brain development.

Olson HE, Poduri A, Pearl PL, et al.
A recurrent de novo PACS2 heterozygous missense variant causes neonatal-onset developmental epileptic encephalopathy, facial dysmorphism, and cerebellar dysgenesis.
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Am J Hum Genet. 2018 Apr 5;102(4):564-570.

The PACS2 Research Foundation is a non-profit organization that is driven to find a treatment for PACS2 syndrome. It strives to help affected patients and their families and spread awareness about the neurodevelopmental disorder. The foundation works closely with researchers around the world to investigate PACS2 syndrome and drive progress towards the development of a treatment.