Identification of Phonology-Related Genes and Functional Characterization of Broca’s and Wernicke’s Regions in Language and Learning Disorders

Abstract

Impaired phonological processing is a leading symptom of multifactorial language and learning disorders suggesting a common biological basis. Here we evaluated studies of dyslexia, dyscalculia, specific language impairment (SLI), and the logopenic variant of primary progressive aphasia (lvPPA) seeking for shared risk genes in Broca’s and Wernicke’s regions, being key for phonological processing within the complex language network. The identified “phonology-related genes” from literature were functionally characterized using Atlas-based expression mapping (JuGEx) and gene set enrichment. Out of 643 publications from the last decade until now, we extracted 21 candidate genes of which 13 overlapped with dyslexia and SLI, six with dyslexia and dyscalculia, and two with dyslexia, dyscalculia, and SLI. No overlap was observed between the childhood disorders and the late-onset lvPPA often showing symptoms of learning disorders earlier in life. Multiple genes were enriched in Gene Ontology terms of the topics learning (CNTNAP2, CYFIP1, DCDC2, DNAAF4, FOXP2) and neuronal development (CCDC136, CNTNAP2, CYFIP1, DCDC2, KIAA0319, RBFOX2, ROBO1). Twelve genes showed above-average expression across both regions indicating moderate-to-high gene activity in the investigated cortical part of the language network. Of these, three genes were differentially expressed suggesting potential regional specializations: ATP2C2 was upregulated in Broca’s region, while DNAAF4 and FOXP2 were upregulated in Wernicke’s region. ATP2C2 encodes a magnesium-dependent calcium transporter which fits with reports about disturbed calcium and magnesium levels for dyslexia and other communication disorders. DNAAF4 (formerly known as DYX1C1) is involved in neuronal migration supporting the hypothesis of disturbed migration in dyslexia. FOXP2 is a transcription factor that regulates a number of genes involved in development of speech and language. Overall, our interdisciplinary and multi-tiered approach provided evidence that genetic and transcriptional variation of ATP2C2, DNAAF4, and FOXP2 may play a role in physiological and pathological aspects of phonological processing.

Vocal learning–associated convergent evolution in mammalian proteins and regulatory elements

“…As expected, we identified much lower rates of diversifying positive selection in the gene with lower rates of evolution in vocal learning species (1.0%) and within the set of randomly chosen transcripts (2.0%). Among the nine genes that showed evidence of positive selection, eight have been associated with neurodevelopment ( CCDC136 , KIDINS220 , LRRN1 , RSG5 , CYLD , GABRA5 , NETO2 , and KIAA1109 ) ( 31 – 38 ). The gene CCDC136 has more directly been associated with multiple language-related phenotypes in humans ( 31 , 39 , 40 ).…”

Characterization of the angular gyrus in an older adult population: a multimodal multilevel approach

“…Generally, area PGa shows a higher expression of ATP2C2 (with higher right as compared to left hemispheric expression) and a lower expression of FOXP2 as compared to area PGp. Since both genes are supposed to support successful language processing during the lifespan [i.e., FOXP2 is supposed to be involved in the development of speech and language, ATP2C2 has been associated with dyslexia and other communication disorders (Lai et al 2003 ; Newbury and Monaco 2010 ; Lambert et al 2011 ; Unger et al 2021a , b )], the difference in gene expression may suggest a functional diversity to exist between areas PGa and PGp. These results, indeed, align with the functional diversity found between these areas, especially in the right hemispheric AG, i.e., area PGa is related to semantic fluency, whereas area PGp shows no correlation with semantic fluency.…”

“…In terms of genetic data, we explored the JuGex tool (Bludau et al 2018 ; https://ebrains.eu/service/jugex/ ). Since previous research claimed the involvement of the AG in language processing, we focused on genetic expression of language-related genes, i.e., FOXP2 and ATP2C2 (Lai et al 2003 ; Newbury and Monaco 2010 ; Lambert et al 2011 ; Unger et al 2021a , b ). While FOXP2 is supposed to be involved in the development of speech and language, ATP2C2 has been associated with dyslexia and other communication disorders (Lai et al 2003 ; Newbury and Monaco 2010 ; Lambert et al 2011 ; Unger et al 2021a , b ).…”

Possible Effects of Acupuncture in Poststroke Aphasia

“…The Broca area primarily refers to the Broadman areas 44 and 45 (BA44 and BA45), namely, the posterior half of the left inferior frontal gyrus [ 31 ]. The Wernicke district refers mainly to the Broadman areas 22, 41, and 42 or the anterior part of the superior temporal gyrus [ 32 , 33 ]. Of those, the Broca area is the sports center of language, so patients with impaired Broca area have impaired language fluency and cannot organize the correct language [ 34 , 35 ].…”