title: Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy.
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.
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, Australia. marinak@anzac.edu.au
authors.forename: Marina L
authors.initials: ML
authors.lastname: Kennerson
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
authors.forename: Bartosz
authors.initials: B
authors.lastname: Kowalski
authors.forename: Julian F B
authors.initials: JF
authors.lastname: Mercer
authors.forename: Jingrong
authors.initials: J
authors.lastname: Tang
authors.forename: Roxana M
authors.initials: RM
authors.lastname: Llanos
authors.forename: Shannon
authors.initials: S
authors.lastname: Chu
authors.forename: Reinaldo I
authors.initials: RI
authors.lastname: Takata
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Speck-Martins
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.forename: Leonardo
authors.initials: L
authors.lastname: Almeida-Souza
authors.forename: Dirk
authors.initials: D
authors.lastname: Fischer
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Philip E
authors.initials: PE
authors.lastname: Taylor
authors.forename: Steven S
authors.initials: SS
authors.lastname: Scherer
authors.forename: Toby A
authors.initials: TA
authors.lastname: Ferguson
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Shawna M E
authors.initials: SM
authors.lastname: Feely
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
authors.forename: James Y
authors.initials: JY
authors.lastname: Garbern
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002675:Child, Preschool; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D017931:DNA Primers / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D005816:Genetic Complementation Test; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016472:Motor Neuron Disease / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D055815:Young Adult
chemical_list: D027682:Cation Transport Proteins; D017931:DNA Primers; D012333:RNA, Messenger; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases