New insight in ARX-mutated patients' language specific impairment and underlying FOXP1 dysregulation

Abstract

Objective: The ARX (Aristaless Related homeoboX) gene encodes a transcription factor which mutations have been associated with syndromes ranging from severe neuronal migration defects such as lissencephaly, to mild or moderate forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent ARX mutation (c.429_452dup24), a duplication of 24 base pairs, constitutes a recognizable clinical syndrome with ARX patients exhibiting ID, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Furthermore, patients also exhibit language impairment and an obvious difficulty to execute oro-lingual praxis. The aim of the present study was to better characterize language abnormalities in ARX c.429_452dup24 patients. Methods: We collected data on 16 French ARX patients, and 16 age- and IQ-matched controls (Fragile X (FraX) patients). Given the similarities between ARX mutated patients and FOXP2-mutated patients, we investigated the molecular relationship between Arx and Foxp2. Results: ARX patients have structural language impairments in both receptive and expressive aspects of language compared to FraX patients: phonetic feature recognition, receptive (ECOSSE test for sentence comprehension) and expressive (TCG-R for sentence production) morphosyntactic skills and oro-lingual dyspraxia (movements of the face, tongue, and lips) were significantly more impaired in ARX patients. FraX patients made words more complex and they were less impaired in their ability to articulate words. On the contrary, language pragmatic analysis showed that ARXdup24 patients had significantly better interactional skills than FraX. patients. Interestingly, we found that although Arx has no effect on Foxp2 expression, Arx was found to activate Foxp1 expression, and that the c.429_452dup24 mutation alters the expression of this gene. Foxp1 is known to heterodimerize with Foxp2 and has been involved in language defects. Conclusion: These data uncover a novel role of ARX in language development, probably through the regulation of Foxp1.