title: Giant axon formation in mice lacking Kell, XK, or Kell and XK: animal models of McLeod neuroacanthocytosis syndrome.
abstract: McLeod neuroacanthocytosis syndrome (MLS) is a rare X-linked multisystem disease caused by XK gene mutations and characterized by hematological and neurological abnormalities. XK, a putative membrane transporter, is expressed ubiquitously and is covalently linked to Kell, an endothelin-3-converting enzyme (ECE-3). Absence of XK results in reduction of Kell at sites where both proteins are coexpressed. To elucidate the functional roles of XK, Kell, and the XK-Kell complex associated with pathogenesis in MLS, we studied the pathology of the spinal cord, anterior roots, sciatic nerve, and skeletal muscle from knockout mouse models, using Kel(-/-), Xk(-/-), Kel(-/-)Xk(-/-), and wild-type mice aged 6 to 18 months. A striking finding was that giant axons were frequently associated with paranodal demyelination. The pathology suggests probable anterograde progression from the spinal cord to the sciatic nerve. The neuropathological abnormalities were found in all three genotypes, but were more marked in the double-knockout Kel(-/-)Xk(-/-) mice than in either Kel(-/-) or Xk(-/-) mice. Skeletal muscles from Xk(-/-) and Kel(-/-)Xk(-/-) mice showed mild abnormalities, but those from Kel(-/-) mice were similar to the wild type. The more marked neuropathological abnormalities in Kel(-/-)Xk(-/-) mice suggest a possible functional association between XK and Kell in nonerythroid tissues.
authors.affiliation: Department of Pathology, Peking University Health Science Center, Beijing, China; New York Blood Center, New York, New York. Electronic address: zhuxiangbjmu@163.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pathology and Laboratory Medicine (Neuropathology), Rutgers University-New Jersey Medical School, Newark, New Jersey.
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Cho
authors.affiliation: New York Blood Center, New York, New York; Department of Cell Line Development, Immunomedics, Morris Plains, New Jersey.
authors.forename: Quan
authors.initials: Q
authors.lastname: Sha
authors.affiliation: New York Blood Center, New York, New York.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Peng
authors.affiliation: New York Blood Center, New York, New York.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Oksov
authors.affiliation: Division of Medical Sciences, National Cancer Center, Singapore.
authors.forename: Siok Yuen
authors.initials: SY
authors.lastname: Kam
authors.affiliation: Division of Medical Sciences, National Cancer Center, Singapore.
authors.forename: Mengfatt
authors.initials: M
authors.lastname: Ho
authors.affiliation: Department of Neurology, James J. Peters VAMC, Bronx, New York; Department of Neurology, Mount Sinai School of Medicine, New York, New York.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Walker
authors.affiliation: New York Blood Center, New York, New York.
authors.forename: Soohee
authors.initials: S
authors.lastname: Lee
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D000072396:Endothelin-Converting Enzymes; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D054546:Neuroacanthocytosis / Q000235:genetics / Q000473:pathology*
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C498286:Xkh protein, mouse; D016282:Aspartic Acid Endopeptidases; C585978:KEL protein, human; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes