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

Abstract

The Schuurs-Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopment Disorder (PACS1-NDD) is a rare autosomal dominant disease caused by mutations in the PACS1 gene. To date, only 87 patients have been reported and, surprisingly, most of them carry the same variant (c.607C>T; p.R203W). The most relevant clinical features of the syndrome include neurodevelopment delay, seizures or a recognizable facial phenotype. Moreover, some of these characteristics overlap with other syndromes, such as the PACS2 or Wdr37 syndromes. The encoded protein phosphofurin acid cluster sorting 1 (PACS-1) is able to bind to different client proteins and direct them to their subcellular final locations. Therefore, although its main function is protein trafficking, it could perform other roles related to its client proteins. In patients with PACS1-NDD, a gain-of-function or a dominant negative mechanism for the mutated protein has been suggested. This, together with the fact that most of the patients carry the same genetic variant, makes it a good candidate for novel therapeutic approaches directed to decreasing the toxic effect of the mutated protein. Some of these strategies include the use of antisense oligonucleotides (ASOs) or targeting of its client proteins.

Unexpected clinical features in an individual with Schuurs-Hoeijmakers syndrome

“…The anorectal (imperforate anus with fistula) and cardiac anomalies (tricuspid insufficiency, persistent left superior vena cava and coronary sinus dilatation) affecting this individual have not been reported previously as part of the SHS (Arnedo et al, 2022). Regarding anorectal anomalies in SHS, only one patient had been described in the literature with ectopic anus, by Tenorio-Castaño et al (2021).…”

“…Schuurs-Hoeijmakers syndrome (SHS) is a neurodevelopmental genetic disorder clinically characterized by recognizable craniofacial features and congenital anomalies mainly affecting the cardiac, genitourinary, and cerebellar systems, and less commonly, the skeletal and ocular (Schuurs-Hoeijmakers et al ., 2016; Arnedo et al ., 2022).…”

“…SHS is caused by heterozygous, gain-of-function, variants in the PACS1 gene. Approximately 87 affected individuals have been described so far, most with the recurrent, heterozygous, de novo PACS1 variant, [NM_018026.3] c.607C>T, p.(Arg203Trp) (Seto et al ., 2021; Arnedo et al ., 2022). Only one additional variant, c.608G>A, p.(Arg203Gln), has been described as associated with SHS so far, also affecting the same residue as the recurrent one (Miyake et al ., 2018; Arnedo et al ., 2022).…”

“…Approximately 87 affected individuals have been described so far, most with the recurrent, heterozygous, de novo PACS1 variant, [NM_018026.3] c.607C>T, p.(Arg203Trp) (Seto et al ., 2021; Arnedo et al ., 2022). Only one additional variant, c.608G>A, p.(Arg203Gln), has been described as associated with SHS so far, also affecting the same residue as the recurrent one (Miyake et al ., 2018; Arnedo et al ., 2022). Experimental models of this variant reinforced the hypothesis that gain-of-function or dominant negative could be mechanisms of disease and supported the role of the PACS1 protein in cranial neural crest migration, which could explain the overlap of craniofacial features amongst affected individuals (Seto et al ., 2021; Arnedo et al ., 2022).…”

Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?

“…PACS1, which is expressed at high levels in the brain during the embryonic period and down regulated in the postnatal period (Liu et al, 2021), mediates protein trafficking from endosomes to the TGN or to the cell surface (Scott et al, 2006). It also has roles in cellular apoptosis, genomic stability, and calcium flux in the endoplasmic reticulum (Arnedo et al, 2022; Thomas et al, 2017). Interacting with acidic clusters that can be phosphorylated by CK2 (casein kinase 2), PACS1 binds to CK2, client proteins, and adaptor proteins, facilitates client and adaptor protein phosphorylation by CK2, and activates CK2 through binding of the CK2 beta subunit (Scott et al, 2006; Thomas et al, 2017).…”