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Intellectual disability and seizures are frequently associated with hypomagnesemia and have an important genetic component. However, to find the genetic origin of intellectual disability and seizures often remains challenging because of considerable genetic heterogeneity and clinical variability. In this study, we have identified new mutations in CNNM2 in five families suffering from mental retardation, seizures, and hypomagnesemia. For the first time, a recessive mode of inheritance of CNNM2 mutations was observed. Importantly, patients with recessive CNNM2 mutations suffer from brain malformations and severe intellectual disability. Additionally, three patients with moderate mental disability were shown to carry de novo heterozygous missense mutations in the CNNM2 gene. To elucidate the physiological role of CNNM2 and explain the pathomechanisms of disease, we studied CNNM2 function combining in vitro activity assays and the zebrafish knockdown model system. Using stable Mg(2+) isotopes, we demonstrated that CNNM2 increases cellular Mg2+ uptake in HEK293 cells and that this process occurs through regulation of the Mg(2+)-permeable cation channel TRPM7. In contrast, cells expressing mutated CNNM2 proteins did not show increased Mg(2+) uptake. Knockdown of cnnm2 isoforms in zebrafish resulted in disturbed brain development including neurodevelopmental impairments such as increased embryonic spontaneous contractions and weak touch-evoked escape behaviour, and reduced body Mg content, indicative of impaired renal Mg(2+) absorption. These phenotypes were rescued by injection of mammalian wild-type Cnnm2 cRNA, whereas mammalian mutant Cnnm2 cRNA did not improve the zebrafish knockdown phenotypes. We therefore concluded that CNNM2 is fundamental for brain development, neurological functioning and Mg(2+) homeostasis. By establishing the loss-of-function zebrafish model for CNNM2 genetic disease, we provide a unique system for testing therapeutic drugs targeting CNNM2 and for monitoring their effects on the brain and kidney phenotype.

SLC25A42 encodes the mitochondrial coenzyme A (CoA) transporter localized at the inner mitochondrial membrane. SLC25A42 deficiency leads to a congenital disease with a heterogeneous clinical presentation, including myopathy, developmental delay, lactic acidosis, and encephalopathy. Twenty‐one patients have been described so far. In the current study, we report on the identification of new biallelic variants in SLC25A42 in three siblings. Patients presented with symmetrical T2 hyperintensity of the putamen with minor volume depression at the brain MRI, elevated lactate, reduced oxygen consumption rates in muscle and fibroblasts, and reduced CoA levels in fibroblasts. Administration of pantothenic acid led to clinical stabilization and increased CoA levels in fibroblasts, thus confirming a role for SLC25A42 in energy metabolism and CoA homeostasis.

Citric acid cycle deficiencies are extremely rare due to their central role in energy metabolism. The ACO2 gene encodes the mitochondrial isoform of aconitase (aconitase 2), the second enzyme of the citric acid cycle. Approximately 100 patients with aconitase 2 deficiency have been reported with a variety of symptoms, including intellectual disability, hypotonia, optic nerve atrophy, cortical atrophy, cerebellar atrophy, and seizures. In this study, a homozygous deletion in the ACO2 gene in two brothers with reduced aconitase 2 activity in fibroblasts has been described with symptoms including truncal hypotonia, optic atrophy, hyperopia, astigmatism, and cerebellar atrophy. In an in vivo trial, triheptanoin was used to bypass the defective aconitase 2 and fill up the citric acid cycle. Motor abilities in both patients improved.

To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into four groups—WNT, SHH, group 3 (G3) and group 4 (G4). However, there is little information about the relevance of pathogenic mitochondrial DNA (mtDNA) mutations and their consequences across these. In this report, we describe the case of a female patient with MB and a mitochondriopathy, followed by a study of mtDNA variants in MB groups. After being diagnosed with G4 MB, the index patient was treated in line with the HIT 2000 protocol with no indications of relapse after five years. Long-term side effects of treatment were complemented by additional neurological symptoms and elevated lactate levels ten years later, resulting in suspected mitochondrial disease. This was confirmed by identifying a mutation in the MT-TS1 gene which appeared homoplasmic in patient tissue and heteroplasmic in the patient’s mother. Motivated by this case, we explored mtDNA mutations across 444 patients from ICGC and HIT cohorts. While there was no statistically significant enrichment of mutations in one MB group, both cohorts encompassed a small group of patients harbouring potentially deleterious mtDNA variants. The case presented here highlights the possible similarities between sequelae caused by MB treatment and neurological symptoms of mitochondrial dysfunction, which may apply to patients across all MB groups. In the context of the current advances in characterising and interpreting mtDNA aberrations, recognising affected patients could enhance our future knowledge regarding the mutations’ impact on carcinogenesis and cancer treatment.

MAN1B1‐CDG is a multisystem disorder caused by mutations in MAN1B1, encoding the endoplasmic reticulum mannosyl‐oligosaccharide alpha‐1,2‐mannnosidase. A defect leads to dysfunction within the degradation of misfolded glycoproteins. We present two additional patients with MAN1B1‐CDG and a resulting defect in endoplasmic reticulum‐associated protein degradation. One patient (P2) is carrying the previously undescribed p.E663K mutation. A therapeutic trial in patient 1 (P1) using disulfiram with the rationale to generate an attenuation of translation and thus a balanced, restored ER glycoprotein synthesis failed. No improvement of the transferrin glycosylation profile was seen.

Polyunsaturated Fatty Acids and Acetoacetate Downregulate the Expression of the ATP-Binding Cassette Transporter A1 Yoshinari Uehara 1 2 3 , Thomas Engel 2 , Zhengchen Li 2 , Christian Goepfert 1 , Stephan Rust 2 , Xiaoqin Zhou 2 , Claus Langer 2 , Christian Schachtrup 4 , Johannes Wiekowski 2 , Stefan Lorkowski 2 , Gerd Assmann 1 2 and Arnold von Eckardstein 1 2 3 1 Institute of Clinical Chemistry and Laboratory Medicine, Central Laboratory, Westphalian Wilhelms-University, Münster, Germany 2 Institute of Arteriosclerosis Research, Münster, Germany 3 University Hospital Zürich, Institute of Clinical Chemistry, Zürich, Switzerland 4 Department of Biochemistry, University of Münster, Münster, Germany Abstract Low HDL cholesterol is a frequent cardiovascular risk factor in diabetes. Because of its pivotal role for the regulation of HDL plasma levels, we investigated in vivo and in vitro regulation of the ATP-binding cassette transporter A1 (ABCA1) by insulin and metabolites accumulating in diabetes. Compared with euglycemic control mice, ABCA1 gene expression was severely decreased in the liver and peritoneal macrophages of diabetic mice. Treatment with insulin restored this deficit. Incubation of cultivated HepG2 hepatocytes and RAW264.7 macrophages with unsaturated fatty acids or acetoacetate, but not with insulin, glucose, saturated fatty acids, or hydroxybutyrate, downregulated ABCA1 mRNA and protein. The suppressive effect of unsaturated fatty acids and acetoacetate became most obvious in cells stimulated with oxysterols or retinoic acid but was independent of the expression of the thereby regulated transcription factors liver-X-receptor α (LXRα) and retinoid-X-receptor α (RXRα), respectively. Unsaturated fatty acids and acetoacetate also reduced ABCA1 promotor activity in RAW264.7 macrophages that were transfected with a 968-bp ABCA1 promotor/luciferase gene construct. As the functional consequence, unsaturated fatty acids and acetoacetate inhibited cholesterol efflux from macrophages. Downregulation of ABCA1 by unsaturated fatty acids and acetoacetate may contribute to low HDL cholesterol and increased cardiovascular risk of diabetic patients. Footnotes Address correspondence and reprint requests to Dr. Arnold von Eckardstein, University Hospital Zürich, Institute of Clinical Chemistry, Rämistrasse 100, CH 8091 Zürich, Switzerland. E-mail: arnold.voneckardstein{at}ikc.usz.ch . Received for publication 30 April 2002 and accepted in revised form12 July 2002. 9- cis- RA, 9- cis- retinoic acid; 22R-HC, 22(R)-hydroxycholesterol; ABCA1, ATP-binding cassette transporter A1; DMEM, Dulbecco’s modified Eagle’s medium; EPA, eicosapentaenoic acid; LXRα, liver-X-receptor α; IFNγ, interferon-γ; PPAR, peroxisome proliferator-activated receptor; PUFA, polyunsaturated fatty acid; RXRα, retinoid-X-receptor α. DIABETES

Tangier disease is characterized by low serum high density lipoproteins and a biochemical defect in the cellular efflux of lipids to high density lipoproteins. ABC1, a member of the ATP-binding cassette family, recently has been identified as the defective gene in Tangier disease. We report here the organization of the human ABC1 gene and the identification of a mutation in the ABC1 gene from the original Tangier disease kindred. The organization of the human ABC1 gene is similar to that of the mouse ABC1 gene and other related ABC genes. The ABC1 gene contains 49 exons that range in size from 33 to 249 bp and is over 70 kb in length. Sequence analysis of the ABC1 gene revealed that the proband for Tangier disease was homozygous for a deletion of nucleotides 3283 and 3284 (TC) in exon 22. The deletion results in a frameshift mutation and a premature stop codon starting at nucleotide 3375. The product is predicted to encode a nonfunctional protein of 1,084 aa, which is approximately half the size of the full-length ABC1 protein. The loss of a Mn/1 restriction site, which results from the deletion, was used to establish the genotype of the rest of the kindred. In summary, we report on the genomic organization of the human ABC1 gene and identify a frameshift mutation in the ABC1 gene of the index case of Tangier disease. These results will be useful in the future characterization of the structure and function of the ABC1 gene and the analysis of additional ABC1 mutations in patients with Tangier disease.

Using a novel gene chip, investigators identified single-nucleotide polymorphisms (SNPs) from three chromosomal regions, including the LPA locus, that were associated with the risk of coronary disease. Two SNPs in LPA were strongly associated with both the level of Lp(a) lipoprotein and the risk of coronary disease. After adjustment for the Lp(a) lipoprotein level, the association with the risk of coronary disease was abolished. These findings support a causal role of an increased Lp(a) lipoprotein level in the risk of coronary disease. Two SNPs in the LPA locus were strongly associated with both the level of Lp(a) lipoprotein and the risk of coronary disease. These findings support a causal role of an increased Lp(a) lipoprotein level in the risk of coronary disease. Genomewide association studies have identified several novel susceptibility loci for coronary artery disease, 1 – 4 but it is likely that only common variants can be detected in this way. 5 , 6 Moreover, loci that are identified with the use of genomewide association studies explain only a small amount of the expected contribution to the risk of coronary disease. The use of arrays of high-density single-nucleotide polymorphisms (SNPs) in candidate genes for cardiovascular disease may help elucidate the genetic contribution to the risk of coronary disease. A recent genomewide association study showed that a cluster of genes — solute carrier family 22 member . . .

SLC25A36 is a pyrimidine nucleotide carrier playing an important role in maintaining mitochondrial biogenesis. Deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction. In human beings, diseases triggered by SLC25A36 mutations have not been described yet. We report the first known case of SLC25A36 deficiency in a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. Whole exome analysis identified the homozygous mutation c.803dupT, p.Ser269llefs*35 in the SLC25A36 gene. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with oral uridine led to an improvement of thyroid function and obstipation, increase of growth and developmental progress. Our findings suggest an important role of SLC25A36 in hormonal regulations and oral uridine as a safe and effective treatment.