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ADHD and other neurodivergent conditions may be caused by deficiency of the lipid flippase ATP9A, which can cause various neural abnormalities with a wide range of effects.

ATP9A is a lipid flippase of the class II P4-ATPases. It is involved in cellular vesicle trafficking and has homozygous variants that are linked to neurodevelopmental disorders. The physiological function, underlying mechanism, and pathophysiological relevance of ATP9A in both humans and animals remain largely unknown. This study, published in Molecular Psychiatry, posits the nonsense mutations c.433C>T/c.658C>T/c.983G>A (p. Arg145*/p. Arg220*/p. Trp328*) in ATP9A (NM_006045.3) as possible causes of autosomal recessive hypotonia, intellectual disability, and attention deficit hyperactivity disorder (ADHD). 

Patients with ADHD who also exhibit intellectual disabilities prove more challenging to treat due to the complex etiology, unclear pathogenic mechanisms, and lack of effective therapeutic drugs. Additionally, the etiology of intellectual disability and ADHD is strongly influenced by genetic factors. The authors propose the study of new pathogenic genes and mechanisms as providing the basis for clinical diagnosis and treatment of this subgroup.

Understanding of ATP9A’s Role in Neurodivergence Is Improving

This study provides a thorough analysis of the features of three individuals from two families who exhibit hypotonia, intellectual disability, ADHD, and other neurological diseases. Whole exon capture sequencing (WES) showed that this disease may be caused by autosomal recessive inheritance of nonsense variants in ATP9A. This gene has not been shown to cause any human disease until 2017, but three recent case reports described biallelic truncating variants in ATP9A as possible causes of neurodevelopmental disorders in humans involving intellectual disability, providing further evidence of this relationship. Additional detailed studies on mice were conducted to confirm and elaborate on the human data.

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The dysregulation of expression and activity of small GTPases, including RAB5 and RAB11,  has also been implicated in other neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. This study confirmed previous study results showing that the activation of RAB11 is needed for the correct location of pericentriolar recycling endosomes and the exit of transferrin from early endosomes to the recycling compartment, in contrast to the role of RAB5 activation, which is required before membrane fusion of early endosomes. 

Neurodegenerative Disorders May Also Be Partially Caused by ATP9A-Related Abnormalities

Various mechanisms for this relationship are described, including ATP9A’s role in the maintenance of neuronal neurite morphology and the viability of neural cells, efficient endosomal recycling in neural cells, and RAB5 and RAB11 activation in vitro and in vivo. The chain of causation from deficiency or mutation of ATP9A to inactivation of RAB5 and RAB11, leading to abnormal endosomal recycling and synaptic dysfunction in the primary motor cortex and hippocampus is suggested and is consistent with findings in both humans and mice. Additional research is needed to understand how or if ATP9A regulates the activity of other RABs, and what the effects of this relationship would be in humans.

Source:

Meng, T., Chen, X., He, Z., Huang, H., Lin, S., Liu, K., Bai, G., Liu, H., Xu, M., Zhuang, H., Zhang, Y., Waqas, A., Liu, Q., Zhang, C., Sun, X. D., Huang, H., Umair, M., Yan, Y., & Feng, D. (2023). ATP9A deficiency causes ADHD and aberrant endosomal recycling via modulating RAB5 and RAB11 activity. Molecular Psychiatry, 1-13. https://doi.org/10.1038/s41380-022-01940-w

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