Somatic mosaicism in Menkes disease suggests choroid plexus-mediated copper transport to the developing brain.
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.
Donsante
Anthony
A
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.
Johnson
Paul
P
Jansen
Laura A
LA
Kaler
Stephen G
SG
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
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
Blood. 2000 Mar 1;95(5):1671-9
10688823
Acta Neuropathol. 2010 Jan;119(1):75-88
20033190
Physiol Rev. 1999 Oct;79(4):1157-91
10508232
J Clin Invest. 1994 Oct;94(4):1657-61
7929843
Adv Pediatr. 1994;41:263-304
7992686
Trends Neurosci. 1990 May;13(5):174-8
1693235
J Med Genet. 2003 Oct;40(10):721-8
14569115
Hum Mol Genet. 1997 Jul;6(7):1043-9
9215673
Anal Chim Acta. 2008 Oct 10;627(2):258-69
18809082
Am J Med Genet A. 2009 Jul;149A(7):1499-503
19530190
Am J Hum Genet. 2001 Jul;69(1):75-87
11410838
J Pediatr. 2006 Sep;149(3):412-5
16939759
Pediatrics. 1962 May;29:764-79
14472668
J Clin Invest. 1994 Apr;93(4):1430-8
8163647
Biometals. 2009 Feb;22(1):177-90
19130269
Nat Genet. 2003 Sep;35(1):70-5
12923530
Am J Hum Genet. 2010 Mar 12;86(3):343-52
20170900
Arch Anat Cytol Pathol. 1998;46(3):153-69
9754371
J Inherit Metab Dis. 1983;6 Suppl 1:59-62
6413776
Nat Genet. 1993 Jan;3(1):14-9
8490646
N Engl J Med. 2008 Feb 7;358(6):605-14
18256395
Nat Rev Genet. 2002 Oct;3(10):748-58
12360233
J Membr Biol. 2003 Jan 1;191(1):1-12
12532272
Am J Hum Genet. 1988 Oct;43(4):355-63
3052049
Clin Chem. 1986 Nov;32(11):2030-3
3096593
Clin Genet. 1982 Dec;22(6):315-20
7160103
PLoS One. 2008 Sep 03;3(9):e3114
18769591
Cell Mol Neurobiol. 2000 Apr;20(2):183-96
10696509
Neurochem Int. 2010 Feb;56(3):451-60
20004225
Electroencephalogr Clin Neurophysiol. 1993 Jul;87(1):57-61
7687955
Ann Neurol. 1993 Feb;33(2):171-5
8434878
Am J Clin Nutr. 1998 May;67(5 Suppl):1029S-1034S
9587147
Biometals. 2007 Jun;20(3-4):233-48
17219055
J Inherit Metab Dis. 2002 Sep;25(5):391-8
12408189
Metab Brain Dis. 2009 Dec;24(4):673-84
19851851
Nat Genet. 1993 Jan;3(1):20-5
8490647
Neuroimage. 2004 Jul;22(3):1046-59
15219577
Am Rev Respir Dis. 1989 Oct;140(4):1097-103
2478056
Mol Genet Metab. 2005 Aug;85(4):291-300
15923132
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6836-41
11391004
Int J Pediatr Otorhinolaryngol. 2007 Jul;71(7):1145-8
17482283
Nat Genet. 1993 Jan;3(1):7-13
8490659
Brain Res. 2009 Jan 12;1248:14-21
19014916
Pediatrics. 1992 Jan;89(1):91-7
1370185
Biochem J. 1986 Aug 15;238(1):177-83
3026340