Heterozygous Missense Variants in the ATPase Phospholipid Transporting 9A Gene, ATP9A , Alter Dendritic Spine Maturation and Cause Dominantly Inherited Nonsyndromic Intellectual Disability

• Published in: Human mutation Vol. 2025; no. 1; p. 7085599
• Main Authors: Cordovado, Amélie, Hérenger, Yvan, Cormier, Coline, López-Martín, Estrella, Stamberger, Hannah, Faivre, Laurence, Denommé-Pichon, Anne-Sophie, Vitobello, Antonio, Abdallah, Hamza Hadj, Barcia, Giulia, Courtin, Thomas, Martínez-Delgado, Beatriz, Bermejo-Sánchez, Eva, Barrero, María J., Gasser, Brooklynn, Bezieau, Stéphane, Küry, Sébastien, Weckhuysen, Sarah, Laumonnier, Frédéric, Toutain, Annick, Vuillaume, Marie-Laure
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2025; Wiley
• Subjects: Antibodies; Dendritic Spines; Dendritic Spines - genetics; Dendritic Spines - metabolism; Dendritic Spines - pathology; Female; Genes; Genetic Association Studies; Genetic Predisposition to Disease; Genomes; HeLa Cells; Heterozygote; Human health and pathology; Humans; Intellectual disabilities; Intellectual Disability; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Life Sciences; Male; Mutagenesis; Mutation, Missense; Patients; Pedigree; Phenotype; Phospholipids; Plasmids; Proteins; Sodium-Potassium-Exchanging ATPase; Sodium-Potassium-Exchanging ATPase - genetics; La Jolla California; Fiji; California; United States > US
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1155/humu/7085599

Intellectual disability is a neurodevelopmental disorder, affecting 2%–3% of the population, with a genetic cause in the majority of cases. ATP9A (Online Mendelian Inheritance in Man (OMIM) ∗ 609126, NM_006045.3) has recently been added to the list of candidate genes involved in this disorder with the identification of biallelic truncating variants in patients with a neurodevelopmental disorder. In this study, we propose a novel mode of inheritance for ATP9A ‐related disorders with the identification of five de novo heterozygous missense variants (p.(Thr393Arg), p.(Glu400Gln), p.(Lys461Glu), p.(Gly552Ala), and p.(His713Asp)), in patients with intellectual disability. In a patient with a similar phenotype, we also identified two truncating variants in ATP9A (p.(Arg145 ∗ ), p.(Glu901 ∗ )), adding a novel family to the six already described in the literature with the recessive mode of inheritance. Functional studies were performed to assess the pathogenicity of these variants. Overexpression of four selected missense mutant forms of Atp9a in HeLa cells and in primary neuronal cultures led to a loss of mature dendritic spines. In HeLa cells, the endosomal localization of the protein encoded by three of these missense variants was preserved whereas the fourth remained blocked in the endoplasmic reticulum. To mimic the effect on neuronal morphology and spine density of nonsense variants, small hairpin RNAs (shRNAs) were used. They induced a decreased expression of ATP9A , affecting the neuronal arborization by decreasing the number of dendrites per neuron. Our results therefore demonstrate the pathogenicity of ATP9A heterozygous missense variants and confirm the role of ATP9A in neuronal maturation and in brain wiring during development. They strengthen the association of ATP9A with neurodevelopmental disorders and demonstrate that a double mode of inheritance should be considered for ATP9A ‐related disorders.