Two novel mutations in the BCKDHB gene that cause maple syrup urine disease

Han, Bing; Han, Bingchao; Guo, Bin; Liu, Yingxia; Cao, Zhiyang

doi:10.1016/j.pedneo.2018.01.006

Cited by 9 publications

(4 citation statements)

References 22 publications

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“…For example, maple syrup urine disease is an autosomal recessive disease that is caused by mutations in one of the three genes encoding components of the BCKDH complex: BCKDHA, BCKDHB, and DBT (Blackburn et al, 2017), resulting in impaired ability to break down BCKAs. Deficiency in BCKDH activity causes elevated urine and plasma BCAAs (Han et al, 2018) and alterations in brain white matter (Klee et al, 2013). It is thought that a lack of BCKDH activity in the liver drives this phenotype based on the finding that transplantation of healthy livers can suppress plasma BCAA accumulation (Wendel et al, 1999).…”

Section: Insights Into Systemic Bcaa Metabolism From Human Genetic Disordersmentioning

confidence: 99%

Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer

2020

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Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer.

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Section: Insights Into Systemic Bcaa Metabolism From Human Genetic Disordersmentioning

confidence: 99%

Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer

2020

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“…MSUD culminates in whole-body accumulation of BCAAs and BCKAs and in pathologic remodeling of amino acid transport in the brain, manifesting in neurologic dysfunction (41). Recent studies have identified several new mutations in the BCKDH E1 subunit a (BCKDHA), BCKDH E2 subunit b (BCKDHB), and dihydrolipoamide branched-chain transacylase E2 (DBT) genes in different population-based studies (42)(43)(44). In a subset of patients, MSUD also results from a loss of function mutation in PPM1K, leading to phosphorylation and inactivation of the E1-a subunit of BCKDH (45).…”

Section: Bckdhmentioning

confidence: 99%

Role of branched‐chain amino acid–catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis

2019

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Beyond their contribution as fundamental building blocks of life, branched‐chain amino acids (BCAAs) play a critical role in physiologic and pathologic processes. Importantly, BCAAs are associated with insulin resistance, obesity, cardiovascular disease, and genetic disorders. However, several metabolome‐wide studies in recent years could not attribute alterations in systemic BCAAs as the sole driver of endocrine perturbations, suggesting that a snapshot of global BCAA changes does not always reveal the underlying modifications. Because enzymes catabolizing BCAAs have a unique distribution, it is plausible that the tissue‐specific roles of BCAA‐catabolic enzymes could precipitate changes in systemic BCAA levels, flux, and action. We review the genetic and pharmacological approaches dissecting the role of BCAA‐catabolic enzyme dysfunctions. We summarized emerging evidence on BCAA metabolic intermediates, tissue specificity of BCAA‐catabolizing enzymes, and crosstalk between different metabolites in driving metabolic maladaptation in health and pathology. This review substantiates the understanding that tissue‐specific dysfunction of the BCAA‐catabolic enzymes and accumulating intermediary metabolites could act as better surrogates of metabolic imbalances, highlighting the biochemical communication among the nutrient triad of BCAAs, glucose, and fatty acid.—Biswas, D., Duffley, L., Pulinilkunnil, T. Role of branched‐chain amino acid–catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis. FASEB J. 33, 8711–8731 (2019). http://www.fasebj.org

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“…MSUD is a highly lethal and disabled genetic metabolic disease, and early diagnosis and treatment can vastly enhance the prognosis process. However, because of the lack of specific clinical manifestations in early MSUD, unscreened newborns with MSUD are highly susceptible to misdiagnosis as sepsis, neurological disorders, and other disorders that cause convulsions (Han et al, 2018;Liu et al, 2018). Therefore, making a diagnosis mainly based on clinical manifestations is difficult, which may lead to delayed treatment of misdiagnosed children.…”

Section: Discussionmentioning

confidence: 99%

Identification of gene mutations in six Chinese patients with maple syrup urine disease

Mao²,

Yang³

et al. 2023

Front. Genet.

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Background: Maple syrup urine disease (MSUD) is a rare autosomal recessive amino acid metabolic disease. This study is to identify the pathogenic genetic factors of six cases of MUSD and evaluates the application value of high-throughput sequencing technology in the early diagnosis of MUSD.Methods: Clinical examination was carried out for patients and used blood tandem mass spectrometry (MS/MS), urine gas chromatography-mass spectrometry (GC/MS), and the application of high-throughput sequencing technology for detection. Validate candidate mutations by polymerase chain reaction (PCR)—Sanger sequencing technology. Bioinformatics software analyzed the variants’ pathogenicity. Using Swiss PDB Viewer software to predict the effect of mutation on the structure of BCKDHA and BCKDHB proteins.Result: A total of six MSUD patients were diagnosed, including four males and two females. Nine variants were found in three genes of six MSUD families by high-throughput sequencing, including four missense mutations: c.659C>T(p.A220V), c.818C>T(p.T273I), c.1134C>G(p.D378E), and c.1006G>A(p.G336S); two non-sense mutations: c.1291C>T(p.R431*) and c.331C>T(p.R111*); three deletion mutations: c.550delT (p.S184Pfs*46), c.718delC (p.P240Lfs*14), and c.795delG (p.N266Tfs*64). Sanger sequencing’s results were consistent with the high-throughput sequencing. The bioinformatics software revealed that the mutations were harmful, and the prediction results of Swiss PDB Viewer suggest that variation affects protein conformation.Conclusion: This study identified nine pathogenic variants in the BCKDHA, BCKDHB, and DBT genes in six MSUD families, including two novel pathogenic variants in the BCKDHB gene, which enriched the genetic mutational spectrum of the disease. High-throughput sequencing is essential for the MSUD’s differential diagnosis, early treatment, and prenatal diagnosis.

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Two novel mutations in the BCKDHB gene that cause maple syrup urine disease

Cited by 9 publications

References 22 publications

Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer

Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer

Role of branched‐chain amino acid–catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis

Identification of gene mutations in six Chinese patients with maple syrup urine disease

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