A novel splice site mutation in AP1S2 gene for X‐linked mental retardation in a Chinese pedigree and literature review

Abstract

Background Pettigrew syndrome ( PGS ) is a rare X‐linked mental retardation that caused by AP 1S2 mutation. The pathogenesis of AP 1S2 deficiency has remained elusive. The purpose of this study is to give a comprehensive overview of the phenotypic and genetic spectrum of AP 1S2 mutations. Methods This study systematically analyzed clinical features and genetic information of a Chinese family with AP 1S2 variation, and reviewed previously reported literatures with the same gene variation. Results We identified a new c.1‐1 G>C mutation in AP 1S2 gene from a four generation family with seven affected individuals and found the elevated neuron‐specific enolase ( NSE ) in a patient. We summarized the clinical manifestation of 59 patients with AP 1S2 mutation. We found that pathogenic point mutations affecting AP 1S2 are associated with dysmorphic features and neurodevelopmental problems, which included highly variable mental retardation ( MR ), delayed in walking, abnormal speech, hypotonia, abnormal brain, abnormal behavior including aggressive behavior, ASD , self‐abusive, and abnormal gait. Patients with splice site mutation were more likely to lead to seizures. By contrast, patients with nonsense mutations are more susceptible to microcephaly. Conclusion Our findings suggest AP 1S2 mutations contribute to a broad spectrum of neurodevelopmental disorders and are important in the etiological spectrum of PGS .

Different types of disease‐causing noncoding variants revealed by genomic and gene expression analyses in families with X‐linked intellectual disability

“…There were 190 Pathogenic or Likely Pathogenic variants in the ClinVar database within the introns upstream of these start codons with a Kozak sequence interrupted by an intron. The clinical features displayed by the brothers in Family 3 were in hindsight consistent with those described in other affected individuals with causative AP1S2 variants (Huo et al, 2019; Tarpey et al, 2006). Individuals with AP1S2 variants display highly variable degrees of ID, even between affected males in the same family.…”

Presynaptic dysfunction in neurodevelopmental disorders: Insights from the synaptic vesicle life cycle

“…The adaptor complex AP‐1 is essential for SV reformation at bulk endosomes (Cheung & Cousin, 2012) and mutations in the gene encoding the σ1B subunit ( AP1S2 ) are responsible for a specific type of X‐linked ID, called Pettigrew Syndrome (Pettigrew, Jackson, & Ledbetter, 1991) (Figure 3). These mutations were either splice site, or nonsense mutations, and were all predicted to be highly pathogenic (Cacciagli, Desvignes, & Girard, 2014; Huo, Teng, Wang, & Liu, 2019; Tarpey et al., 2006). Deletion of the Ap1s2 gene in mice results in an activity‐dependent accumulation of bulk endosomes, with a concomitant decrease in SV number and recycling pool replenishment, in agreement with its key role in SV generation via ADBE (Glyvuk, Tsytsyura, & Geumann, 2010).…”

Novel Molecular Hallmarks of Group 3 Medulloblastoma by Single-Cell Transcriptomics

“…Of note, GRM8 expression has been shown to characterize Group 4 MB ( 47 ) which overlaps in molecular features with Group 3 tumors. AP1S2 is a component of adaptor protein complex 1, and AP1S2 mutation could cause various brain diseases, including hydrocephalus and Dandy-Walker malformation, among others ( 31 ). To the best of our knowledge, this is the first study to reveal the functional significance of AP1S2 in Group 3 MB.…”

“…The marker genes of this specific cluster were selected, followed by validation and selection, performed with tumor samples from 33 patients with Group 3 MB. Consequently, we unearthed the GRM8 gene, encoding metabotropic glutamate receptor 8 (MGLUR8), a G-protein coupled glutamate receptor reported to significantly influence the risk of central nervous system (CNS) disease (28)(29)(30), and the AP1S2 gene, encoding AP-1 complex subunit sigma-2, a component of adaptor protein complex 1 and correlating with CNS disorder (31), as novel hallmarks linked to poor prognosis of Group 3 MB. Thus, our findings identified GRM8 and AP1S2 as potential targets for treatment of patients with MYC+ Group 3 MB in the future.…”