Universitätspublikationen
Refine
Document Type
- Article (2)
Language
- English (2) (remove)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
- autism (2) (remove)
Institute
- Medizin (2) (remove)
The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.
Abstract: The Children's Communication Checklist-2 (CCC-2) is often applied to assess pragmatic language impairment which is highly prevalent in autism spectrum disorder (ASD) and several mental health conditions. We replicated previous findings on the limited applicability of the CCC-2 in clinical samples and the inconsistent findings concerning the factor structure. The aim of the present study was, thus, to develop a concise, simplified, and revised version of the CCC-2 in a large German-speaking sample. Four groups of children and adolescents aged 4 to 17 years were included: ASD (n = 195), intellectual disability (ID, n = 83), diverse mental health conditions (MHC, n = 144) and a typically developing control group (TD, n = 417). We reduced the original number of items from 70 to 39, based on item analysis, exploratory factor analysis and the exclusion of communication-unrelated items. The revised version, CCC-R (α = 0.96), consists of two empirically derived factors: a pragmatic-language (α = 0.96) and a grammatical-semantic-language factor (α = 0.93). All clinical groups (ASD, ID, and MHC) had significantly increased CCC-R total scores, with the highest scores being in the neurodevelopmental disorder groups (ASD and ID). In addition, we found group-specific patterns of elevated pragmatic-language scores in the ASD group and grammatical-semantic scores in the ID group. The CCC-R was comparable to the CCC-2 in distinguishing ASD from the other groups. The CCC-R is proposed as a simplified and easily applied, clinical questionnaire for caregivers, assessing pragmatic language impairments across neurodevelopmental disorders and mental health conditions. Lay Summary: The CCC-2 is a questionnaire designed to identify children who have problems in the social use of language, however, it is limited in its clinical application and exhibits inconsistent factors. We have created a shorter and simpler version of the CCC-2 that we have called the CCC-R which overcomes the previous limitations of the CCC-2. It consists of two subscales: pragmatic language and grammatical-semantic language. The CCC-R can be used as a short and clinically relevant caregiver questionnaire which assesses pragmatic language impairments in children and adolescents. Autism Res 2021, 14: 759–772. © 2021 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals LLC.