A novel mutation in the SLC25A15 gene in a Turkish patient with HHH syndrome: Functional analysis of the mutant protein

Tunalı, Nagehan Ersoy; Marobbio, C; Tiryakioglu, Necip Ozan; Punzi, Giuseppe; Saygılı, Seha; Önal, Hasan; Palmieri, Ferdinando

doi:10.1016/j.ymgme.2014.03.002

Cited by 25 publications

(16 citation statements)

References 39 publications

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“…However, normal brain CT scan or MRI findings were reported in several patients, mainly in those who did not experience an overt hyperammonemic coma [36,40,60]. Interestingly, multiple stroke-like lesions were reported in a 4 year-old patient presenting irritability, vomiting, highly elevated liver enzymes, hyperammonemia, and coagulopathy [56].…”

Section: Resultsmentioning

confidence: 99%

The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Martinelli

Diodato

Ponzi

et al. 2015

Orphanet J Rare Dis

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BackgroundHyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia.MethodsA systematic review of publications reporting patients with HHH syndrome was performed.ResultsWe retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life.ConclusionsThis paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0242-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Martinelli

Diodato

Ponzi

et al. 2015

Orphanet J Rare Dis

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“…Control cultures with the empty vector were processed in parallel. Inclusion bodies were purified on sucrose density gradient and washed at 4°C, first with TE buffer (10 mM Tris/HCl, 1 mM EDTA, pH 8), then twice with a buffer containing Triton X-114 (2% w/v) and 10 mM HEPES, pH 8, and, finally, with HEPES 10 mM, pH 7.5 (48). Proteins were solubilized in 2% (w/v) Sarkosyl and purified by centrifugation and Ni 2ϩ -nitrilotriacetic acid-agarose affinity chromatography, as described previously (49).…”

Section: Methodsmentioning

confidence: 99%

Characterization of Human and Yeast Mitochondrial Glycine Carriers with Implications for Heme Biosynthesis and Anemia

Lunetti

Damiano

Benedetto

et al. 2016

Journal of Biological Chemistry

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Heme is an essential molecule in many biological processes, such as transport and storage of oxygen and electron transfer as well as a structural component of hemoproteins. Defects of heme biosynthesis in developing erythroblasts have profound medical implications, as represented by sideroblastic anemia. The synthesis of heme requires the uptake of glycine into the mitochondrial matrix where glycine is condensed with succinyl coenzyme A to yield ␦-aminolevulinic acid. Herein we describe the biochemical and molecular characterization of yeast Hem25p and human SLC25A38, providing evidence that they are mitochondrial carriers for glycine. In particular, the hem25⌬ mutant manifests a defect in the biosynthesis of ␦-aminolevulinic acid and displays reduced levels of downstream heme and mitochondrial cytochromes. The observed defects are rescued by complementation with yeast HEM25 or human SLC25A38 genes. Our results identify new proteins in the heme biosynthetic pathway and demonstrate that Hem25p and its human orthologue SLC25A38 are the main mitochondrial glycine transporters required for heme synthesis, providing definitive evidence of their previously proposed glycine transport function. Furthermore, our work may suggest new therapeutic approaches for the treatment of congenital sideroblastic anemia.

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“…Among the 38 different mutations found to cause HHH syndrome, the most common are p.Phe188del and p.Arg179*, which are found in 45% of the patients. The effects of many disease-causing mutations on ORC1-catalyzed transport have been assessed in reconstituted liposomes by the EPRA method and by in vitro cell culture studies, which have shown that, with very few exceptions, the mutations are deleterious for activity [111,[115][116][117]. Some of the mutations (p.Glu180Lys, p.Arg275Gly and p.Arg275Gln at positions 183 and 279) ( Figure 2B,D) are in the contact points (Figure 1), changing residues that were proved experimentally to participate directly in substrate binding [31].…”

Section: Slc25a15 (Ornithine Carrier 1 Orc1) Deficiencymentioning

confidence: 99%

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

2020

Self Cite

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In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.

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A novel mutation in the SLC25A15 gene in a Turkish patient with HHH syndrome: Functional analysis of the mutant protein

Cited by 25 publications

References 39 publications

The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Characterization of Human and Yeast Mitochondrial Glycine Carriers with Implications for Heme Biosynthesis and Anemia

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

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