Functional Properties of Rare Missense Variants of Human CDH13 Found in Adult Attention Deficit/Hyperactivity Disorder (ADHD) Patients

Abstract

The CDH13 gene codes for T-cadherin, a GPI-anchored protein with cell adhesion properties that is highly expressed in the brain and cardiovascular system. Previous studies have suggested that CDH13 may be a promising candidate gene for Attention Deficit/Hyperactivity Disorder (ADHD). The aims of this study were to identify, functionally characterize, and estimate the frequency of coding CDH13 variants in adult ADHD patients and controls. We performed sequencing of the CDH13 gene in 169 Norwegian adult ADHD patients and 63 controls and genotyping of the identified variants in 641 patients and 668 controls. Native and green fluorescent protein tagged wild type and variant CDH13 proteins were expressed and studied in CHO and HEK293 cells, respectively. Sequencing identified seven rare missense CDH13 variants, one of which was novel. By genotyping, we found a cumulative frequency of these rare variants of 2.9% in controls and 3.2% in ADHD patients, implying that much larger samples are needed to obtain adequate power to study the genetic association between ADHD and rare CDH13 variants. Protein expression and localization studies in CHO cells and HEK293 cells showed that the wild type and mutant proteins were processed according to the canonical processing of GPI-anchored proteins. Although some of the mutations were predicted to severely affect protein secondary structure and stability, no significant differences were observed between the expression levels and distribution of the wild type and mutant proteins in either HEK293 or CHO cells. This is the first study where the frequency of coding CDH13 variants in patients and controls is reported and also where the functional properties of these variants are examined. Further investigations are needed to conclude whether CDH13 is involved in the pathogenesis of ADHD or other conditions.

Cdh13 and AdipoQ gene knockout alter instrumental and Pavlovian drug conditioning

“…GWASs have also identified associations between several single nucleotide polymorphisms (SNPs) in CDH13 and multiple behavioral disorders as well, including ADHD (Lesch et al , 2008, Mavroconstanti et al , 2013, Neale et al , 2010, Salatino-Oliveira et al , 2015), bipolar disorder symptoms (Cho et al , 2015), schizophrenia (Borglum et al , 2014) violent behavior (Tiihonen et al , 2015) and alterations in working memory performance (Arias-Vásquez & Altink, 2011). CDH13 is also associated with subjective response to amphetamine in non-addicted subjects (Hart et al , 2012b, Leventhal et al , 2016); which may be an intermediate phenotype of drug abuse.…”

“…Recently the CDH13 gene, which codes for the cell-adhesion molecule cadherin-13 (Ranscht & Dours-Zimmermann 1991) or T-Cadherin, has received attention for its relationship to substance abuse (Johnson et al 2011;Liu et al 2006;Uhl et al 2008a) and smoking cessation outcomes (Drgon et al 2009). GWASs have also identified associations between several single nucleotide polymorphisms in CDH13 and multiple behavioral disorders as well, including ADHD (Lesch et al 2008;Mavroconstanti et al 2013;Neale et al 2010;Salatino-Oliveira et al 2015), bipolar disorder symptoms (Cho et al 2015), schizophrenia (Borglum et al 2014), violent behavior (Tiihonen et al 2015), and alterations in working memory performance (Arias-Vásquez et al 2011). CDH13 is also associated with subjective response to amphetamine in non-addicted subjects (Hart et al 2012b;Leventhal et al 2017), which may be an intermediate phenotype of drug abuse.…”

An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility

“…Studies on dopamine transporter (DAT1) (37-40), tryptophan hydroxylase 2 (TPH2) (41, 42) and T-cadherin (CDH13) (43) have examined the functional properties of rare missense mutations of moderate and large effects, but these findings fail to explain the higher incidence of ADHD and larger phenotypic variance observed in populations. Instead, the common disease-common variant hypothesis is better supported by a substantial number of genetic epidemiological studies, with common variants accounting for ~40% of ADHD heritability (7, 8).…”

In Silico Analysis of Functional Single Nucleotide Polymorphisms in the Human TRIM22 Gene

“…However, according to the ternary classification system (SVM3), a large decrease in protein stability corresponds to a DDG <−0.5 and a large increase in protein stability corresponds to a DDG >0.5. In contrast, DDG values that fall between −0.5 and 0.5 correspond to relatively neutral protein stability [62], [63]. The pH was set to 7 and the temperature was set to 25°C for all submissions.…”