Molecular and pathological basis of aceruloplasminemia

Aceruloplasminemia is an autosomal recessive neurodegenerative disease characterized by iron accumulation in the brain as well as visceral organs. It is a loss-of-function disorder caused by mutations in the ceruloplasmin gene. Clinically, this disease consists of the triad of adult-onset neurologic...

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Autores principales:	KONO,SATOSHI, MIYAJIMA,HIROAKI
Lenguaje:	English
Publicado:	Sociedad de Biología de Chile 2006
Materias:	ceruloplasmin iron lipid peroxidation mutation
Acceso en línea:	http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602006000100003
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spelling	oai:scielo:S0716-976020060001000032006-06-30Molecular and pathological basis of aceruloplasminemiaKONO,SATOSHIMIYAJIMA,HIROAKI ceruloplasmin iron lipid peroxidation mutation Aceruloplasminemia is an autosomal recessive neurodegenerative disease characterized by iron accumulation in the brain as well as visceral organs. It is a loss-of-function disorder caused by mutations in the ceruloplasmin gene. Clinically, this disease consists of the triad of adult-onset neurological disease, retinal degeneration and diabetes mellitus. Massive iron accumulation and extensive loss of neurons are observed in the basal ganglia. The elevated iron concentration is associated with increased lipid peroxidation in the brains of aceruloplasminemia patients. Enlarged or deformed astrocytes and spheroid-like globular structures are characteristic neuropathological findings in aceruloplasminemia. Moreover, deformed astrocytes and globular structures react positively to anti-4-hydroxynonenal antibody, suggesting that increased oxidative stress is involved in neuronal cell death in aceruloplasminemia brain. More than 30 aceruloplasminemia-causing mutations in the ceruloplasmin gene have been identified. We examined the biosynthesis of two missense ceruloplasmin proteins that result from a Japanese P177R mutation and a Dutch G631R mutation, using Chinese hamster ovary cell expression system. The P177R mutant protein is retained in the endoplasmic reticulum. The G631R mutant protein, predicted to alter the interactions at a single type I copper-binding site, prevented incorporation of copper into apoceruloplasmin and resulted in the synthesis and secretion only of apoceruloplasmin. Molecular analysis of missense mutations showed different structure-function relationships in ceruloplasmin protein. The investigation of mutant ceruloplasmin reveals new insights into molecular pathogenesis of aceruloplasminemia as well as biosynthesis, trafficking, and function of ceruloplasmin.info:eu-repo/semantics/openAccessSociedad de Biología de ChileBiological Research v.39 n.1 20062006-01-01text/htmlhttp://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602006000100003en10.4067/S0716-97602006000100003
institution	Scielo Chile
collection	Scielo Chile
language	English
topic	ceruloplasmin iron lipid peroxidation mutation
spellingShingle	ceruloplasmin iron lipid peroxidation mutation KONO,SATOSHI MIYAJIMA,HIROAKI Molecular and pathological basis of aceruloplasminemia
description	Aceruloplasminemia is an autosomal recessive neurodegenerative disease characterized by iron accumulation in the brain as well as visceral organs. It is a loss-of-function disorder caused by mutations in the ceruloplasmin gene. Clinically, this disease consists of the triad of adult-onset neurological disease, retinal degeneration and diabetes mellitus. Massive iron accumulation and extensive loss of neurons are observed in the basal ganglia. The elevated iron concentration is associated with increased lipid peroxidation in the brains of aceruloplasminemia patients. Enlarged or deformed astrocytes and spheroid-like globular structures are characteristic neuropathological findings in aceruloplasminemia. Moreover, deformed astrocytes and globular structures react positively to anti-4-hydroxynonenal antibody, suggesting that increased oxidative stress is involved in neuronal cell death in aceruloplasminemia brain. More than 30 aceruloplasminemia-causing mutations in the ceruloplasmin gene have been identified. We examined the biosynthesis of two missense ceruloplasmin proteins that result from a Japanese P177R mutation and a Dutch G631R mutation, using Chinese hamster ovary cell expression system. The P177R mutant protein is retained in the endoplasmic reticulum. The G631R mutant protein, predicted to alter the interactions at a single type I copper-binding site, prevented incorporation of copper into apoceruloplasmin and resulted in the synthesis and secretion only of apoceruloplasmin. Molecular analysis of missense mutations showed different structure-function relationships in ceruloplasmin protein. The investigation of mutant ceruloplasmin reveals new insights into molecular pathogenesis of aceruloplasminemia as well as biosynthesis, trafficking, and function of ceruloplasmin.
author	KONO,SATOSHI MIYAJIMA,HIROAKI
author_facet	KONO,SATOSHI MIYAJIMA,HIROAKI
author_sort	KONO,SATOSHI
title	Molecular and pathological basis of aceruloplasminemia
title_short	Molecular and pathological basis of aceruloplasminemia
title_full	Molecular and pathological basis of aceruloplasminemia
title_fullStr	Molecular and pathological basis of aceruloplasminemia
title_full_unstemmed	Molecular and pathological basis of aceruloplasminemia
title_sort	molecular and pathological basis of aceruloplasminemia
publisher	Sociedad de Biología de Chile
publishDate	2006
url	http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602006000100003
work_keys_str_mv	AT konosatoshi molecularandpathologicalbasisofaceruloplasminemia AT miyajimahiroaki molecularandpathologicalbasisofaceruloplasminemia
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Molecular and pathological basis of aceruloplasminemia

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