Association of CDH11 with Autism Spectrum Disorder Revealed by Matched-gene Co-expression Analysis and Mouse Behavioral Studies

Abstract

A large number of putative risk genes for autism spectrum disorder (ASD) have been reported. The functions of most of these susceptibility genes in developing brains remain unknown, and causal relationships between their variation and autism traits have not been established. The aim of this study was to predict putative risk genes at the whole-genome level based on the analysis of gene co-expression with a group of high-confidence ASD risk genes (hcASDs). The results showed that three gene features – gene size, mRNA abundance, and guanine-cytosine content – affect the genome-wide co-expression profiles of hcASDs. To circumvent the interference of these features in gene co-expression analysis, we developed a method to determine whether a gene is significantly co-expressed with hcASDs by statistically comparing the co-expression profile of this gene with hcASDs to that of this gene with permuted gene sets of feature-matched genes. This method is referred to as "matched-gene co-expression analysis" (MGCA). With MGCA, we demonstrated the convergence in developmental expression profiles of hcASDs and improved the efficacy of risk gene prediction. The results of analysis of two recently-reported ASD candidate genes, CDH11 and CDH9, suggested the involvement of CDH11, but not CDH9, in ASD. Consistent with this prediction, behavioral studies showed that Cdh11-null mice, but not Cdh9-null mice, have multiple autism-like behavioral alterations. This study highlights the power of MGCA in revealing ASD-associated genes and the potential role of CDH11 in ASD.

Cdh11: Roles in different diseases and potential value in disease diagnosis and treatment

“…Subsequent research discovered altered CDH11 expression in individuals with ASD, further suggesting that changes in its expression may partially contribute to the pathological process of ASD. In line with this, behavioral studies conducted on mice with CDH11 deficiency revealed a range of autism-like behavioral changes [ 91 ], providing further confirmation of the significance of CDH11 in ASD.…”

“…To date, a total of 7 molecularly confirmed cdh11 -related cases of EWS have been reported, originating from 5 families, including two sisters from a consanguineous couple, a male child, an Indian female, a sibling pair, and a male individual from Japan. Homozygous variants in cdh11 were identified in these patients, confirming EWS as an autosomal recessive disorder, wherein one of its causal factors is attributed to loss-of-function variants in cdh11 [ [91] , [92] , [93] , [94] ]. However, it is important to emphasize that the current understanding of cdh11 in relation to this syndrome remains limited, necessitating further validation of its reliability.…”

“… [ 9 , 11 ] Liver fibrosis The activation of hepatic stellate cells. TGFβ/Smad [ [68] , [69] , [70] ] Cardiac fibrosis MAPKs CaMKII-STAT3 √（SYN0012） [ [71] , [72] , [73] , [74] , [75] ] Rheumatoid Arthritis Regulate cell-cell contacts and in vitro invasive abilities of FLS TNF-α，IL-1β，MAPK，NF-κB，IL-6，MMPs [ 78 , [80] , [81] , [82] ] Systemic sclerosis Promotes the process of skin fibrosis TGF-β [ 83 , 84 ] Calcific aortic valve disease Involved in the calcification of the aortic valve RhoA/Sox9 ✓ [ 71 , [86] , [87] , [88] , [89] ] Autism Spectrum Disorder Participate in disease development [ 21 , 90 , 91 ] ElsahyWaters syndrome One of its causal factors is attributed to loss-of-function variants in CDH11. [ [91] , [92] , [93] ...…”

Gene editing in monogenic autism spectrum disorder: animal models and gene therapies

“…Heterozygous Arid1b knockout (hKO) mice exhibit ASD-like traits associated with social behavior, anxiety, and persistence, as well as weight loss, impaired motor coordination, and hydrocephalus (Shibutani et al, 2017 ). Chd11 -null mice, but not Chd9 -null mice, have multiple autism-like behavioral changes (Wu N. et al, 2021 ). The small or missing regions of the anterior commissure of Tbr1 +/– mice lead to defective neuronal differentiation in the amygdala, which may serve as a suitable model for determining how autism genes control neuronal circuits, neural activity, and behaviors (Huang et al, 2019 ).…”

Genetic ablation of metabotropic glutamate receptor 5 in rats results in an autism-like behavioral phenotype

“…Although the exact etiology of ASD remains an enigma, at least 30% of cases have an underlying genetic etiology [28][29][30][31][32][33][34][35]. The most common gene variants involved in ASD include SHANK3, MECP2, NLGN3, NRXN1 and FMR1 [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50], some of which are regulated by the metabotropic glutamate receptor (mGluR) pathway, especially mGluR5, thus making it a very attractive target for understanding the pathogenesis of ASD [51].…”