Extending the phenotypic spectrum of Sengers syndrome: Congenital lactic acidosis with synthetic liver dysfunction

Beck, David B.; Cusmano‐Ozog, Kristina; Andescavage, Nickie; Leon, Eyby

doi:10.3233/trd-180020

Cited by 8 publications

(8 citation statements)

References 10 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%

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%

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

2021

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“…The clinical manifestation of Sengers syndrome closely resembles that of mitochondrial ATP synthesis disorder and cardiolipin metabolism deficiency. The predominant symptoms of the disease are congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis (Mayr et al, 2012;Beck et al, 2018). Patients with severe cases die in infancy, while people with mild cases can survive for decades (Haghighi et al, 2014).…”

Section: Agk and Sengers Syndromementioning

confidence: 99%

“…An increasing number of reports have investigated families with Sengers syndrome and via whole-exome sequencing identified different types of mutations in the AGK gene, and patients with different AGK mutations show clinical heterogeneity (Mayr et al, 2012;Siriwardena et al, 2013;Haghighi et al, 2014;Beck et al, 2018;Aggarwal et al, 2021). Adenine nucleotide transporter 1 (ANT1, also known as SLC25A4) is a mitochondrial protein with dual functions.…”

Section: Agk and Sengers Syndromementioning

confidence: 99%

Acylglycerol Kinase-Targeted Therapies in Oncology

Chu

Hong

Zheng

2021

Front. Cell Dev. Biol.

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Acylglycerol kinase (AGK) is a recently discovered mitochondrial lipid kinase, and mutation of its gene is the fundamental cause of Sengers syndrome. AGK is not only involved in the stability of lipid metabolism but also closely related to mitochondrial protein transport, glycolysis, and thrombocytopoiesis. Evidence indicates that AGK is an important factor in the occurrence and development of tumors. Specifically, AGK has been identified as an oncogene that partakes in the regulation of tumor cell growth, invasion, metastasis, and drug resistance. The versatility of AGK and its unique role in different types of cancerous and normal cells greatly piqued our interest. We believe that AGK is a promising target for cancer therapy. Therefore, this review summarizes the main research advances concerning AGK, including the discovery of its physiological/pathogenic mechanisms, and provides a reference for the feasible evaluation of AGK as a therapeutic target for human diseases, particularly tumors.

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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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Extending the phenotypic spectrum of Sengers syndrome: Congenital lactic acidosis with synthetic liver dysfunction

Cited by 8 publications

References 10 publications

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

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

Acylglycerol Kinase-Targeted Therapies in Oncology

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

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