AUTS2 Syndrome: Molecular Mechanisms and Model Systems

Abstract

AUTS2 syndrome is a genetic disorder that causes intellectual disability, microcephaly, and other phenotypes. Syndrome severity is worse when mutations involve 3’ regions (exons 9-19) of the AUTS2 gene. Human AUTS2 protein has two major isoforms, full-length (1259 aa) and C-terminal (711 aa), the latter produced from an alternative transcription start site in exon 9. Structurally, AUTS2 contains the putative “AUTS2 domain” (∼200 aa) conserved among AUTS2 and its ohnologs, fibrosin, and fibrosin-like-1. Also, AUTS2 contains extensive low-complexity sequences and intrinsically disordered regions, features typical of RNA-binding proteins. During development, AUTS2 is expressed by specific progenitor cell and neuron types, including pyramidal neurons and Purkinje cells. AUTS2 localizes mainly in cell nuclei, where it regulates transcription and RNA metabolism. Some studies have detected AUTS2 in neurites, where it may regulate cytoskeletal dynamics. Neurodevelopmental functions of AUTS2 have been studied in diverse model systems. In zebrafish, auts2a morphants displayed microcephaly. In mice, excision of different Auts2 exons (7, 8, or 15) caused distinct phenotypes, variously including neonatal breathing abnormalities, cerebellar hypoplasia, dentate gyrus hypoplasia, EEG abnormalities, and behavioral changes. In mouse embryonic stem cells, AUTS2 could promote or delay neuronal differentiation. Cerebral organoids, derived from an AUTS2 syndrome patient containing a pathogenic missense variant in exon 9, exhibited neocortical growth defects. Emerging technologies for analysis of human cerebral organoids will be increasingly useful for understanding mechanisms underlying AUTS2 syndrome. Questions for future research include whether AUTS2 binds RNA directly, how AUTS2 regulates neurogenesis, and how AUTS2 modulates neural circuit formation.

auts2 Features and Expression Are Highly Conserved during Evolution Despite Different Evolutionary Fates Following Whole Genome Duplication

“…It should, however, be noted that most species eventually lost one of the two copies, suggesting that a single copy of the gene is sufficient. When looking at the auts2 gene structure and predicted protein coding size and domains, we observed that in teleost fish (as highlighted here in medaka and zebrafish in Figure 4 ), the auts2a gene encodes for a long (1282 and 1278 amino acids in medaka and zebrafish, respectively) protein that is highly similar to the human AUTS2 protein [ 4 ]. The human gene is also known to encode many alternatively spliced variants.…”

“…To investigate conserved sequence features between species, amino acid sequences (accession numbers available in Tables S5 and S6 ) were aligned using the BioEdit software (version 7.0.5.3, Raleigh, NC, USA) and conserved domains were visually identified based on existing data [ 4 ].…”

“…The AUTS2 gene (activator of transcription and developmental regulator, previously known as autism susceptibility candidate 2) is associated with multiple neurodevelopmental disorders (NDDs) and neurological disorders (see [ 1 , 2 , 3 , 4 ] for a recent review). AUTS2 was originally linked to autism spectrum disorders (ASDs) [ 5 ] and subsequently associated with other intellectual disabilities, short stature, microcephaly, cerebral palsy, facial dimorphism [ 6 ], developmental delays [ 7 ], mental retardation [ 8 ], speech and language disorders [ 9 ], addictive behavior [ 10 ], and schizophrenia [ 11 ].…”

“…The human AUTS2 gene encodes a full-length protein of 1259 amino acids [ 6 ]. While numerous splice variants have been described, the best documented variants encode for a 786-amino-acid (S-AUTS2-Var1) protein and a 711-amino-acid (S-AUTS2-Var2) protein, both corresponding to the C-terminal portion of the full-length protein [ 2 , 4 , 6 ]. In humans, AUTS2 is expressed in various tissues including the fetal brain [ 5 ].…”

“…It was however hypothesized that AUTS2 could function as a transcriptional activator or repressor depending on the cellular context [ 2 , 14 , 15 ]. In the nucleus, AUTS2 was also hypothesized to interact with RNA, either directly or through RNA binding proteins to ultimately regulate neuronal differentiation [ 4 , 15 , 16 ]. Finally, Auts2 is also able to regulate cytoskeletal dynamics in the cytoplasm to ultimately regulate neurite outgrowth and branch formation, as well as neuronal formation in mice [ 17 ].…”