A functional framework in patient fibroblasts informs ATP7A variant pathogenicity and identifies p.Q990P as a novel cause of distal motor neuropathy.

Gonzalo Perez-Siles, Bianca R Grosz, Melina Ellis, Jonathan Baets, Ataf Sabir, Mary O'Driscoll, Rita Horvath, Kleopas A Kleopa, Sharon La Fontaine, Pontus Gourdon, Steve Vucic, Marina L Kennerson

Journal: Human molecular genetics 2026;35(14):

PMID: 42418840

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Abstract

ATP7A is a P-type ATPase copper transporter and a central component of the intracellular network to maintain copper (Cu) homeostasis, trafficking between the trans-Golgi network (TGN) and the cell periphery in response to intracellular Cu levels. Pathogenic ATP7A variants cause Menkes disease (MNK), occipital horn syndrome (OHS) and X-linked distal hereditary motor neuropathy (HMNX), with the clinical severity inversely related to residual ATP7A function. In MNK and OHS, variants result in loss of ATP7A function due to absent (MNK) or markedly reduced (OHS) protein levels, leading to abolished ATP7A trafficking and/or impaired Cu transport capacity. HMNX-associated variants are thought to retain partial Cu transport activity, although functional data remain limited. To date, three missense variants (p.T994I, p.P1386S, p.A991D) are established causes of HMNX, but the number of ATP7A variants reported in patients with a distal motor neuropathy phenotype is increasing, creating a need for functional assessment of variants of uncertain significance (VUS). We have developed a functional framework for evaluating HMNX-associated ATP7A variants. Using three patient fibroblast lines carrying the confirmed variants, we demonstrate reduced ATP7A TGN localization under low-Cu conditions and impaired capacity of these cell lines to maintain intracellular Cu levels. By applying these assays to five VUS (p.R703H, p.Y760C, p.A768G, p.Q990P, p.M1311V) identified in individuals from unsolved peripheral neuropathy families, we identify p.Q990P as a novel ATP7A variant in a patient with progressive peripheral motor neuropathy. This approach enables comparison of Cu trafficking and handling across ATP7A alleles, providing a functional framework to support diagnostic variant classification.

Address: School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia.; Northcott Neuroscience Laboratory, ANZAC Research Institute, Gate 3 Hospital Road, Sydney Local Health District, Sydney, NSW 2139, Australia.; Northcott Neuroscience Laboratory, ANZAC Research Institute, Gate 3 Hospital Road, Sydney Local Health District, Sydney, NSW 2139, Australia.; Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, Antwerp 2610, Belgium.; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, Antwerp 2610, Belgium.; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Drie Eikenstraat 655, Antwerp 2650, Belgium.; West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2TG, United Kingdom.; Clinical Genetics Unit, Birmingham Women's and Children's NHS Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2TG, United Kingdom.; Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Robinson Way, Cambridge CB2 0PY, United Kingdom.; Neuroscience Department, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, Ayios Dometios, Nicosia 2371, Cyprus.; Center for Neuromuscular Disorders, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, Ayios Dometios, Nicosia 2371, Cyprus.; School of Life and Environmental Sciences, Deakin University, 221 Burwood Highway, Burwood, VIC 3125, Australia.; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen 2200, Denmark.; Department of Experimental Medical Science, Faculty of Medicine, Lund University, Biomedical Centre (BMC I13), Sölvegatan 19, Lund SE-221 84, Sweden.; Concord Clinical School, Faculty of Medicine and Health, University of Sydney and Brain and Nerve Research Centre, Concord Repatriation General Hospital, Hospital Road, Sydney, NSW 2139, Australia.; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia.; Northcott Neuroscience Laboratory, ANZAC Research Institute, Gate 3 Hospital Road, Sydney Local Health District, Sydney, NSW 2139, Australia.; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Hospital Road, Sydney, NSW, 2139 Australia.

DOI: 10.1093/hmg/ddag061

MeSH Terms: Humans, Copper-Transporting ATPases, Fibroblasts, Copper, Menkes Kinky Hair Syndrome, trans-Golgi Network, Cutis Laxa, Ehlers-Danlos Syndrome, Mutation, Missense, Muscular Atrophy, Spinal, Genetic Diseases, X-Linked, Protein Transport