Journal article
Missense Mutations in the Copper Transporter Gene ATP7A Cause X-Linked Distal Hereditary Motor Neuropathy
American journal of human genetics, Vol.86(3), pp.343-352
2010
DOI: 10.1016/j.ajhg.2010.01.027
PMCID: PMC2833394
PMID: 20170900
Abstract
Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included
ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique
ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a
S. cerevisiae copper transport knockout. Although
ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function.
Details
- Title: Subtitle
- Missense Mutations in the Copper Transporter Gene ATP7A Cause X-Linked Distal Hereditary Motor Neuropathy
- Creators
- Marina L Kennerson - Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, AustraliaGarth A Nicholson - Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, AustraliaStephen G Kaler - Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USABartosz Kowalski - Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, AustraliaJulian F.B Mercer - Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, AustraliaJingrong Tang - Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USARoxana M Llanos - Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, AustraliaShannon Chu - Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, AustraliaReinaldo I Takata - Sarah Network Rehabilitation Hospitals, Brasilia, DF, BrazilCarlos E Speck-Martins - Sarah Network Rehabilitation Hospitals, Brasilia, DF, BrazilJonathan Baets - Department of Molecular Genetics, Flanders Institute for Biotechnologie and University of Antwerp, Antwerpen, BelgiumLeonardo Almeida-Souza - Department of Molecular Genetics, Flanders Institute for Biotechnologie and University of Antwerp, Antwerpen, BelgiumDirk Fischer - Department of Neurology, University Hospital Basel and Department of Neuropediatrics, University Children's Hospital Basel, Basel, SwitzerlandVincent Timmerman - Department of Molecular Genetics, Flanders Institute for Biotechnologie and University of Antwerp, Antwerpen, BelgiumPhilip E Taylor - Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, AustraliaSteven S Scherer - Department of Neurology, University of Pennsylvania, Philadelphia, PA, USAToby A Ferguson - Department of Neurology, University of Pennsylvania, Philadelphia, PA, USAThomas D Bird - Departments of Neurology and Medical Genetics, University of Washington School of Medicine, Seattle, WA, USAPeter De Jonghe - Department of Molecular Genetics, Flanders Institute for Biotechnologie and University of Antwerp, Antwerpen, BelgiumShawna M.E Feely - Department of Neurology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USAMichael E Shy - Department of Neurology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USAJames Y Garbern - Department of Neurology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.86(3), pp.343-352
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.ajhg.2010.01.027
- PMID
- 20170900
- PMCID
- PMC2833394
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Language
- English
- Date published
- 2010
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984020787402771
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