New Disorder of Copper Metabolism Identified, Caused by Variants in CTR1 Gene

A novel missense mutation in identical twins leads to discovery and definition of new inherited disorder of brain copper metabolism.

August 18, 2022

Copper is essential for many cellular functions, including cellular respiration, antioxidant defense, neurotransmitter biosynthesis and neuropeptide amidation, among others. Until recently, only two inborn errors of copper metabolism were well established. Both are rare. Wilson's disease and Menkes disease result from mutations in the copper-transporting P-type ATPases; ATP7B and ATP7A, respectively.

CTR1 is a high-affinity copper uptake protein essential for mammalian development and copper homeostasis, as well as progression of certain cancers. Until recently, no cases of human CTR1 deficiency were reported.

Now, in a study published in Human Molecular Genetics, Stephen Kaler, MD, MPH, and his colleagues report the first description of CTR1 deficiency due to a homozygous missense mutation of the CTR1 gene in two children. They also present the associated clinical, biochemical and molecular phenotypes of this deficiency.

Identical twin boys with the same missense mutation in the CTR1 gene both presented with hypotonia, global developmental delay, seizures and rapid brain atrophy after appearing well for the first two months of life. Brain imaging indicated more atrophy than in children with untreated Menkes disease.

The team used clinical phenotyping, brain imaging, assays for copper, cytochrome c oxidation and mitochondrial respiration, western blotting, cell transfection experiments, confocal and electron microscopy, protein structure modeling and fetal brain and cerebral organoid transcriptome analyses.

“This paper represents the culmination of an extraordinary international collaboration spanning contributions from five countries and eight different institutions, all focused on efforts to diagnose, understand, and treat two infants with a previously unrecognized inborn error of human copper metabolism,” said Dr. Kaler, senior author of the publication and principal investigator in the Center for Gene Therapy at the Abigail Wexner Research Institute.

The team also evaluated the effects of copper histidinate in the patients’ cultured cells and, under a formal research protocol, in the patients themselves.

“In the cell cultures, the copper histidinate treatment normalized cytochrome c oxidase activity and enhanced mitochondrial respiration,” said Dr. Kaler. “In the patients, we saw modest clinical improvements. Growth improved and serum copper levels increased, but overall clinical improvements were limited, possibly because of pathology sustained before the treatment was initiated.”

In combination with present and prior studies, these infants’ clinical, biochemical and molecular phenotypes establish the impact of this novel variant on copper metabolism and cellular homeostasis and illuminate a crucial role for CTR1 in human brain development. CTR1 deficiency represents a newly defined inherited order of brain copper metabolism.

“The research findings are highly relevant to our further understanding of copper transport into and within the brain and may lead to advances in developing remedies for this disorder and other human illnesses, including cancer,” Dr. Kaler says. “We are indebted to these children and their devoted parents for participating in this study.”

Reference:

Batzios S, Tal G, DiStasio AT, Peng Y, Charalambous C, Nicolaides P, Kamsteeg E-J, Korman SH, Mandel H, Steinbach PJ, Yi L, Fair SR, Hester ME, Drousiotou A, Kaler SG. Newly identified disorder of copper metabolism caused by variants in CTR1, a high-affinity copper transporter. Human Molecular Genetics. 2022;1-10.

About Nationwide Children’s Hospital

Named to the Top 10 Honor Roll on U.S. News & World Report’s 2021-22 list of “Best Children’s Hospitals,” Nationwide Children’s Hospital is one of America’s largest not-for-profit free-standing pediatric health care systems providing unique expertise in pediatric population health, behavioral health, genomics and health equity as the next frontiers in pediatric medicine, leading to best outcomes for the health of the whole child. Integrated clinical and research programs, as well as prioritizing quality and safety, are part of what allows Nationwide Children’s to advance its unique model of care. Nationwide Children’s has a staff of more than 13,000 that provides state-of-the-art wellness, preventive and rehabilitative care and diagnostic treatment during more than 1.3 million patient visits annually. As home to the Department of Pediatrics of The Ohio State University College of Medicine, Nationwide Children’s physicians train the next generation of pediatricians and pediatric specialists. The Abigail Wexner Research Institute at Nationwide Children’s Hospital is one of the Top 10 National Institutes of Health-funded free-standing pediatric research facilities. More information is available at NationwideChildrens.org

About Nationwide Children's Hospital

Named to the Top 10 Honor Roll on U.S. News & World Report’s 2021-22 list of “Best Children’s Hospitals,” Nationwide Children’s Hospital is one of America’s largest not-for-profit free-standing pediatric health care systems providing unique expertise in pediatric population health, behavioral health, genomics and health equity as the next frontiers in pediatric medicine, leading to best outcomes for the health of the whole child. Integrated clinical and research programs, as well as prioritizing quality and safety, are part of what allows Nationwide Children’s to advance its unique model of care. Nationwide Children’s has a staff of more than 13,000 that provides state-of-the-art wellness, preventive and rehabilitative care and diagnostic treatment during more than 1.6 million patient visits annually. As home to the Department of Pediatrics of The Ohio State University College of Medicine, Nationwide Children’s physicians train the next generation of pediatricians and pediatric specialists. The Abigail Wexner Research Institute at Nationwide Children’s Hospital is one of the Top 10 National Institutes of Health-funded free-standing pediatric research facilities. More information is available at NationwideChildrens.org.