Somatic mosaicism in Menkes disease suggests choroid plexus-mediated copper transport to the developing brain

Anthony Donsante, Paul Johnson, Laura A. Jansen, Stephen G. Kaler

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2529-2534
Number of pages6
JournalAmerican Journal of Medical Genetics, Part A
Volume152 A
Issue number10
DOIs
StatePublished - Oct 2010
Externally publishedYes

Fingerprint

Menkes Kinky Hair Syndrome
Choroid Plexus
Mosaicism
Copper
Brain
Ectoderm
Mutation
Mesoderm
Cerebrospinal Fluid
Epithelium
Endothelial Cells
Neural Plate
Gastrulation
Endoderm
Missense Mutation
Blood-Brain Barrier
Catecholamines
Blood Cells
Central Nervous System
Fibroblasts

Keywords

  • ATP7A
  • Choroid plexus
  • Copper metabolism
  • Menkes disease
  • Somatic mosaicism

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Medicine(all)

Cite this

Somatic mosaicism in Menkes disease suggests choroid plexus-mediated copper transport to the developing brain. / Donsante, Anthony; Johnson, Paul; Jansen, Laura A.; Kaler, Stephen G.

In: American Journal of Medical Genetics, Part A, Vol. 152 A, No. 10, 10.2010, p. 2529-2534.

Research output: Contribution to journalArticle

Donsante, Anthony ; Johnson, Paul ; Jansen, Laura A. ; Kaler, Stephen G. / Somatic mosaicism in Menkes disease suggests choroid plexus-mediated copper transport to the developing brain. In: American Journal of Medical Genetics, Part A. 2010 ; Vol. 152 A, No. 10. pp. 2529-2534.
@article{89c59eae0cbe471080030b5d7e77ea8f,
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.",
keywords = "ATP7A, Choroid plexus, Copper metabolism, Menkes disease, Somatic mosaicism",
author = "Anthony Donsante and Paul Johnson and Jansen, {Laura A.} and Kaler, {Stephen G.}",
year = "2010",
month = "10",
doi = "10.1002/ajmg.a.33632",
language = "English (US)",
volume = "152 A",
pages = "2529--2534",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "10",

}

TY - JOUR

T1 - Somatic mosaicism in Menkes disease suggests choroid plexus-mediated copper transport to the developing brain

AU - Donsante, Anthony

AU - Johnson, Paul

AU - Jansen, Laura A.

AU - Kaler, Stephen G.

PY - 2010/10

Y1 - 2010/10

N2 - 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.

AB - 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.

KW - ATP7A

KW - Choroid plexus

KW - Copper metabolism

KW - Menkes disease

KW - Somatic mosaicism

UR - http://www.scopus.com/inward/record.url?scp=78349272389&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78349272389&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.33632

DO - 10.1002/ajmg.a.33632

M3 - Article

VL - 152 A

SP - 2529

EP - 2534

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 10

ER -