Mutation in the AGK gene in two siblings with unusual Sengers syndrome

Allali, Sanae; Dorboz, Imen; Samaan, Simon; Slama, Abdelhamid; Rambaud, Charlène; Boespflug‐Tanguy, Odile; Sarret, Catherine

doi:10.1007/s11011-017-0101-6

Cited by 12 publications

(10 citation statements)

References 24 publications

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“…All rights reserved Sengers syndrome is an autosomal recessive disorder characterised by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis ( Table 1) [ [107][108][109][110][111][112][113][114][115]. Sengers syndrome is caused by a variety of mutations in the TIM22 complex component AGK, including missense, nonsense and frameshift mutations [107][108][109][110][111][112][113][114][115]. The severity of the phenotype varies significantly, even within families with the same mutation, although it should be noted that the less affected sibling in this case received intervention at an early age potentially affecting disease progression [113].…”

Section: Accepted Articlementioning

confidence: 99%

“…Sengers syndrome is an autosomal recessive disorder characterised by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis (Table 1) [107][108][109][110][111][112][113][114][115]. Sengers syndrome is caused by a variety of mutations in the TIM22 complex component AGK, including missense, nonsense and frameshift mutations [107][108][109][110][111][112][113][114][115].…”

Section: Agk and Sengers Syndromementioning

confidence: 99%

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Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co‐ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.

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Section: Accepted Articlementioning

confidence: 99%

Section: Agk and Sengers Syndromementioning

confidence: 99%

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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“…Supplementary Material 1 | Gene structure of AGK and localization of identified mutations (1)(2)(3)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Red font indicates newly reported mutations.…”

Section: Data Availability Statementmentioning

confidence: 99%

“…The AGK gene is located on chromosome 7q34 and consists of 16 exons (1). To date, several studies have identified different types of loss-of-function mutations in the AGK gene, including start codon mutations, nonsense, frameshift, and splice site mutations (1)(2)(3)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). AGK is a mitochondrial protein that catalyzes the phosphorylation of diacylglycerol (DAG) and monoacylglycerol (MAG) to phosphatidic acid (PA) and lysophosphatidic acid (LPA), respectively.…”

Section: Introductionmentioning

confidence: 99%

Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene

Wang

Shan

et al. 2021

Front. Pediatr.

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Sengers syndrome (OMIM #212350) is a rare autosomal recessive disorder due to mutations in acylglycerol kinase (AGK) gene. We report two cases that were diagnosed clinically and confirmed genetically. Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation. Genetic testing of a boy revealed a homozygous pathogenic variant for Sengers syndrome in AGK (c.1131+2T>C) which was classified as likely pathogenic according to the ACMG guideline; besides, his skeletal muscle biopsy and transmission electron microscope presented obvious abnormity. One girl had compound heterozygous (c.409C>T and c.390G>A) variants of AGK gene that was identified in the proband and further Sanger sequencing indicated that the parents carried a single heterozygous mutation each. After the administration of “cocktail” therapy including coenzyme Q10, carnitine, and vitamin B complex, as well as ACEI, heart failure and myopathy of the boy were significantly improved and the condition was stable after 1-year follow-up, while the cardiomyopathy of the girl is not progressive but the plasma lactate acid increased significantly. We present the first report of two infants with Sengers syndrome diagnosed via exome sequencing in China.

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“…Interestingly, and although AGK was not yet described as a component of the TIM22 complex, decreased levels of Adenine nucleotide transporter 1 (a metabolite carrier) were reported for Sengers syndrome patients [ 101 , 190 ]. Additional studies in patients presenting with various forms of this syndrome, identified already described or new mutations in the AGK gene (p.M1I, p.K327*, p.I175Yfs*2, c.424-1G>A, p.R137*, p.I346Yfs*39, p.L75Qfs*12, p.R281*, p.Q291*, c.877+3G>T, p.Q291*, p.F406Vfs*4) [ 102 , 103 , 104 , 105 ]. Two independent studies characterized AGK as a component of the TIM22 complex and showed that this lipid kinase was required for proper metabolite carrier import into the inner membrane [ 167 , 168 ].…”

Section: Defects In Carrier Transport Associated With Diseasementioning

confidence: 99%

Molecular Insights into Mitochondrial Protein Translocation and Human Disease

Ruiz‐Pesini

Montoya

Pacheu-Grau

2021

Genes

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In human mitochondria, mtDNA encodes for only 13 proteins, all components of the OXPHOS system. The rest of the mitochondrial components, which make up approximately 99% of its proteome, are encoded in the nuclear genome, synthesized in cytosolic ribosomes and imported into mitochondria. Different import machineries translocate mitochondrial precursors, depending on their nature and the final destination inside the organelle. The proper and coordinated function of these molecular pathways is critical for mitochondrial homeostasis. Here, we will review molecular details about these pathways, which components have been linked to human disease and future perspectives on the field to expand the genetic landscape of mitochondrial diseases.

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Mutation in the AGK gene in two siblings with unusual Sengers syndrome

Cited by 12 publications

References 24 publications

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene

Molecular Insights into Mitochondrial Protein Translocation and Human Disease

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