Congenital cataract, muscular hypotonia, developmental delay and sensorineural hearing loss associated with a defect in copper metabolism

Horváth, Rita; Freisinger, Peter; Rubio, R.; Merl, T.; Bax, R.; Mayr, Johannes A.; Shawan,; Müller-Höcker, J.; Pongratz, D.; Møller, Lisbeth Birk; Horn, Nina; Jaksch, Michaela

doi:10.1007/s10545-005-0479-x

Cited by 24 publications

(17 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Horvath et al, in 2005, were the first to report this phenotype where they also identified Cytochrome C Oxidase (COX) deficiency in tissue in addition. Though the patient succumbed to the illness, they observed complete reversal of COX deficiency with copper histidinate supplementation (Horváth et al 2005).But a follow up study with four additional cases did not report COX deficiency in any of the patients (Huppke et al 2012). In our patient too, histopathology did not reveal any COX deficiency but showed a relatively low functioning of complex IV on spectrophotometric analysis.…”

Section: Discussionmentioning

confidence: 96%

Huppke-Brendel syndrome in a seven months old boy with a novel 2-bp deletion in SLC33A1

et al. 2016

View full text Add to dashboard Cite

Huppke -Brendel syndrome is a new addition to the evolving spectrum of copper metabolism defects. It is an autosomal recessive disorder characterized by congenital cataract, impaired hearing, and developmental delay with low copper and ceruloplasmin. It is caused by defects in SLC33A1 that codes for acetyl CoA transporter protein. Reports on variation in this gene causing human disease is extremely scarce and the metabolic link between this gene and copper metabolism is yet to be identified. Here we report a seven months old infant with Huppke-Brendel Syndrome. In addition to the already reported features, he also had hypo pigmented hair and hypogonadism. His magnetic resonance imaging revealed hypo myelination and cerebellar hypoplasia. Clinical exome sequencing revealed a homozygous two base pair deletion, c.542_543delTG (p.Val181GlyfsTer6) in exon 1 of the SLC33A1. This report expands the phenotypic and genotypic spectrum of Huppke Brendel syndrome.

show abstract

Section: Discussionmentioning

confidence: 96%

Huppke-Brendel syndrome in a seven months old boy with a novel 2-bp deletion in SLC33A1

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The integrity of this signaling pathway is compromised by mutations in SCO1 and SCO2 (28,45,46). SCO1 and SCO2 patients present with clinically heterogeneous forms of fatal disease that affect liver, heart, or brain function (47)(48)(49)(50)(51)(52)(53)(54). Affected tissues in SCO patients are both COX-and copper-deficient, and both deficiencies appear to be key components of the underlying tissue specificity of disease (46,55).…”

Section: Discussionmentioning

confidence: 99%

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

Boulet

Vest

Maynard

et al. 2018

Journal of Biological Chemistry

109

View full text Add to dashboard Cite

Edited by Ruma BanerjeeCopper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2. Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo.Mitochondrial dysfunction contributes to the pathogenesis of heart failure, neurodegenerative disorders, myopathies, and diabetes (1). Mitochondria are dynamic, double membranebound organelles with a semi-permeable outer membrane that allows exchange of metabolites between the cytosol and the intermembrane space (IMS).5 In contrast, the inner membrane (IM) that separates the IMS and the matrix is tightly sealed. Thus, numerous transporters are required to provide the matrix with a diverse range of substrates that are necessary to support metabolism, the biogenesis of iron-sulfur clusters, and the assembly of the electron transport chain (ETC) required for oxidative phosphorylation (2).Cytochrome c oxidase (COX) is the terminal electron-accepting complex of the ETC. Mammalian COX contains 14 major subunits, two of which bind three redox centers required for electron transfer (3). The catalytic core consists of the mitochondrially-encoded subunits COX1, COX2, and COX3. COX2 binds the binuclear Cu A site required for accepting electrons from cytochrome c. These electrons are then transferred to the cofactors of COX1, first to heme a and then to the heme a 3 -Cu B site where oxygen is bound. COX biogenesis requires Ͼ25 accessory proteins known as COX assembly factors (1). The overwhelming majority of ETC defects that underlie mitochondrial dysfunction and human disease is caused by pathogenic mutations in accessory factors (1). At least nine of these factors facilitate the insertion of the copper cofactors that are essential for the catalytic competence of the COX holoenzyme (4). In yeast, it has been demonstrated that the copper used for COX assembly comes from the matrix, and this matrix copper pool is conserved in mammals (5, 6). Howe...

show abstract

“…Urine copper was normal. Horváth et al had previously reported one of those patients, whose muscle biopsies revealed a dilated sarcoplasmic reticulum as the most conspicuous finding [ 128 ]. Huppke-Brendel syndrome is caused by mutations in the SLC33A1 gene, encoding for a transporter (AT-1) that translocates acetyl-CoA into the ER lumen [ 127 ].…”

Section: Copper Homeostasismentioning

confidence: 99%

Disorders of metal metabolism

Ferreira

Gahl

2017

TRD

View full text Add to dashboard Cite

Trace elements are chemical elements needed in minute amounts for normal physiology. Some of the physiologically relevant trace elements include iodine, copper, iron, manganese, zinc, selenium, cobalt and molybdenum. Of these, some are metals, and in particular, transition metals. The different electron shells of an atom carry different energy levels, with those closest to the nucleus being lowest in energy. The number of electrons in the outermost shell determines the reactivity of such an atom. The electron shells are divided in sub-shells, and in particular the third shell has s, p and d sub-shells. Transition metals are strictly defined as elements whose atom has an incomplete d sub-shell. This incomplete d sub-shell makes them prone to chemical reactions, particularly redox reactions. Transition metals of biologic importance include copper, iron, manganese, cobalt and molybdenum. Zinc is not a transition metal, since it has a complete d sub-shell. Selenium, on the other hand, is strictly speaking a nonmetal, although given its chemical properties between those of metals and nonmetals, it is sometimes considered a metalloid. In this review, we summarize the current knowledge on the inborn errors of metal and metalloid metabolism.

show abstract

Congenital cataract, muscular hypotonia, developmental delay and sensorineural hearing loss associated with a defect in copper metabolism

Cited by 24 publications

References 31 publications

Huppke-Brendel syndrome in a seven months old boy with a novel 2-bp deletion in SLC33A1

Huppke-Brendel syndrome in a seven months old boy with a novel 2-bp deletion in SLC33A1

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

Disorders of metal metabolism

Contact Info

Product

Resources

About