title: Somatic mosaicism in Menkes disease suggests choroid plexus-mediated copper transport to the developing brain.
abstract: The primary mechanism of copper transport to the brain is unknown, although this process is drastically impaired in Menkes disease, an X-linked neurodevelopmental disorder caused by mutations in an evolutionarily conserved copper transporter, ATP7A. Potential central nervous system entry routes for copper include brain capillary endothelial cells that originate from mesodermal angioblasts and form the blood-brain barrier, and the choroid plexuses, which derive from embryonic ectoderm, and form the blood-cerebrospinal fluid barrier. We exploited a rare (and first reported) example of somatic mosaicism for an ATP7A mutation to shed light on questions about copper transport into the developing brain. In a 20-month-old Menkes disease patient evaluated before copper treatment, blood copper, and catecholamine concentrations were normal, whereas levels in cerebrospinal fluid were abnormal and consistent with his neurologically severe phenotype. We documented disparate levels of mosaicism for an ATP7A missense mutation, P1001L, in tissues derived from different embryonic origins; allele quantitation showed P1001L in approximately 27% of DNA samples from blood cells (mesoderm-derived) and 88% from cultured fibroblasts (ectoderm-derived). These findings imply that the P1001L mutation in the patient preceded formation of the three primary embryonic lineages at gastrulation, with the ectoderm layer ultimately harboring a higher percentage of mutation-bearing cells than mesoderm or endoderm. Since choroid plexus epithelia are derived from neuroectoderm, and brain capillary endothelial cells from mesodermal angioblasts, the clinical and biochemical findings in this infant support a critical role for the blood-CSF barrier (choroid plexus epithelia) in copper entry to the developing brain.
authors.affiliation: Unit on Human Copper Metabolism, Molecular Medicine Program, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1853, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Donsante
authors.forename: Paul
authors.initials: P
authors.lastname: Johnson
authors.forename: Laura A
authors.initials: LA
authors.lastname: Jansen
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D019943:Amino Acid Substitution; D001692:Biological Transport / Q000235:genetics; D001706:Biopsy; D001812:Blood-Brain Barrier; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics*; D003300:Copper / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000652:urine; D000073840:Copper-Transporting ATPases; D004247:DNA / Q000097:blood / Q000235:genetics; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004475:Ectoderm / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics* / Q000473:pathology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000378:metabolism; D009030:Mosaicism; D009154:Mutation; D020125:Mutation, Missense; D012016:Reference Values; D012867:Skin / Q000473:pathology; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D001613:beta 2-Microglobulin; D008734:Methoxyhydroxyphenylglycol; D004295:Dihydroxyphenylalanine; D003300:Copper; D004247:DNA; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; C010117:3,4-dihydroxyphenylglycol
references.citation: Blood. 2000 Mar 1;95(5):1671-9
references.pmid: 10688823
references.citation: Acta Neuropathol. 2010 Jan;119(1):75-88
references.pmid: 20033190
references.citation: Physiol Rev. 1999 Oct;79(4):1157-91
references.pmid: 10508232
references.citation: J Clin Invest. 1994 Oct;94(4):1657-61
references.pmid: 7929843
references.citation: Adv Pediatr. 1994;41:263-304
references.pmid: 7992686
references.citation: Trends Neurosci. 1990 May;13(5):174-8
references.pmid: 1693235
references.citation: J Med Genet. 2003 Oct;40(10):721-8
references.pmid: 14569115
references.citation: Hum Mol Genet. 1997 Jul;6(7):1043-9
references.pmid: 9215673
references.citation: Anal Chim Acta. 2008 Oct 10;627(2):258-69
references.pmid: 18809082
references.citation: Am J Med Genet A. 2009 Jul;149A(7):1499-503
references.pmid: 19530190
references.citation: Am J Hum Genet. 2001 Jul;69(1):75-87
references.pmid: 11410838
references.citation: J Pediatr. 2006 Sep;149(3):412-5
references.pmid: 16939759
references.citation: Pediatrics. 1962 May;29:764-79
references.pmid: 14472668
references.citation: J Clin Invest. 1994 Apr;93(4):1430-8
references.pmid: 8163647
references.citation: Biometals. 2009 Feb;22(1):177-90
references.pmid: 19130269
references.citation: Nat Genet. 2003 Sep;35(1):70-5
references.pmid: 12923530
references.citation: Am J Hum Genet. 2010 Mar 12;86(3):343-52
references.pmid: 20170900
references.citation: Arch Anat Cytol Pathol. 1998;46(3):153-69
references.pmid: 9754371
references.citation: J Inherit Metab Dis. 1983;6 Suppl 1:59-62
references.pmid: 6413776
references.citation: Nat Genet. 1993 Jan;3(1):14-9
references.pmid: 8490646
references.citation: N Engl J Med. 2008 Feb 7;358(6):605-14
references.pmid: 18256395
references.citation: Nat Rev Genet. 2002 Oct;3(10):748-58
references.pmid: 12360233
references.citation: J Membr Biol. 2003 Jan 1;191(1):1-12
references.pmid: 12532272
references.citation: Am J Hum Genet. 1988 Oct;43(4):355-63
references.pmid: 3052049
references.citation: Clin Chem. 1986 Nov;32(11):2030-3
references.pmid: 3096593
references.citation: Clin Genet. 1982 Dec;22(6):315-20
references.pmid: 7160103
references.citation: PLoS One. 2008 Sep 03;3(9):e3114
references.pmid: 18769591
references.citation: Cell Mol Neurobiol. 2000 Apr;20(2):183-96
references.pmid: 10696509
references.citation: Neurochem Int. 2010 Feb;56(3):451-60
references.pmid: 20004225
references.citation: Electroencephalogr Clin Neurophysiol. 1993 Jul;87(1):57-61
references.pmid: 7687955
references.citation: Ann Neurol. 1993 Feb;33(2):171-5
references.pmid: 8434878
references.citation: Am J Clin Nutr. 1998 May;67(5 Suppl):1029S-1034S
references.pmid: 9587147
references.citation: Biometals. 2007 Jun;20(3-4):233-48
references.pmid: 17219055
references.citation: J Inherit Metab Dis. 2002 Sep;25(5):391-8
references.pmid: 12408189
references.citation: Metab Brain Dis. 2009 Dec;24(4):673-84
references.pmid: 19851851
references.citation: Nat Genet. 1993 Jan;3(1):20-5
references.pmid: 8490647
references.citation: Neuroimage. 2004 Jul;22(3):1046-59
references.pmid: 15219577
references.citation: Am Rev Respir Dis. 1989 Oct;140(4):1097-103
references.pmid: 2478056
references.citation: Mol Genet Metab. 2005 Aug;85(4):291-300
references.pmid: 15923132
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6836-41
references.pmid: 11391004
references.citation: Int J Pediatr Otorhinolaryngol. 2007 Jul;71(7):1145-8
references.pmid: 17482283
references.citation: Nat Genet. 1993 Jan;3(1):7-13
references.pmid: 8490659
references.citation: Brain Res. 2009 Jan 12;1248:14-21
references.pmid: 19014916
references.citation: Pediatrics. 1992 Jan;89(1):91-7
references.pmid: 1370185
references.citation: Biochem J. 1986 Aug 15;238(1):177-83
references.pmid: 3026340