Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome

Yoo, Dong Hyun; Choi, Young Chul; Nam, Da Eun; Choi, Sun Seong; Kim, Ji Won; Choi, Byung Ok; Chung, Ki Wha

doi:10.1016/j.mito.2017.05.005

Cited by 42 publications

(25 citation statements)

References 19 publications

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“…Notably, the clinical phenotypes of our patients largely overlap with those of patients carrying FASTKD2 mutations (Table 1) previously reported (Ghezzi et al, 2008; Yoo et al, 2017). However, a few symptoms described earlier were absent in our patients.…”

Section: Discussionsupporting

confidence: 73%

“…However, the lack of optic atrophy does not seem to be an essential diagnostic requirement for FASTKD2 mutation‐associated mitochondrial diseases. Besides, epileptic seizures were reported as the primary symptom at onset in patients carrying FASTKD2 mutation (Ghezzi et al, 2008; Yoo et al, 2017), of note, our Patient 1 did not experience epileptic and generalized tonic‐clonic seizures. Although increased blood serum lactate concentration was detected in all patients from previous studies, the respective values were normal in our three patients (Table 1).…”

Section: Discussionsupporting

confidence: 49%

“…Loss of FASTKD2 was shown to result in a significant decrease in mitochondrial RNA and compromised mitochondrial respiration owing to impairment of the activity of mitochondrial complexes I, III, IV, and V (Popow et al, 2015). Therefore, it is interesting to examine if FASTKD2 mutation can cause multiple mitochondrial complex deficiency, other than isolated complex IV deficiency (Ghezzi et al, 2008; Yoo et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Mutations inFASTKD2are associated with mitochondrial disease with multi‐OXPHOS deficiency

Wei

et al. 2020

Human Mutation

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Mutations in FASTKD2, a mitochondrial RNA binding protein, have been associated with mitochondrial encephalomyopathy with isolated complex IV deficiency. However, deficiencies related to other oxidative phosphorylation system (OXPHOS) complexes have not been reported. Here, we identified three novel FASTKD2 mutations, c.808_809insTTTCAGTTTTG, homoplasmic mutation c.868C>T, and heteroplasmic mutation c.1859delT/c.868C>T, in patients with mitochondrial encephalomyopathy.Cell-based complementation assay revealed that these three FASTKD2 mutations were pathogenic. Mitochondrial functional analysis revealed that mutations in FASTKD2 impaired the mitochondrial function in patient-derived lymphocytes due to the deficiency in multi-OXPHOS complexes, whereas mitochondrial complex II remained unaffected. Consistent results were also found in human primary muscle cell and zebrafish with knockdown of FASTKD2. Furthermore, we discovered that FASTKD2 mutation is not inherently associated with epileptic seizures, optic atrophy, and loss of visual function. Alternatively, a patient with FASTKD2 mutation can show sinus tachycardia and hypertrophic cardiomyopathy, which was partially confirmed in zebrafish with knockdown of FASTKD2. In conclusion, both in vivo and in vitro studies suggest that loss of function mutation in FASTKD2 is responsible for multi-OXPHOS complexes deficiency, and FASTKD2-associated mitochondrial disease has a high degree of clinical heterogenicity.FASTKD2, metabolic genetic diseases, mitochondrial disease, OXPHOS complex Xiujuan Wei, Miaomiao Du, and Dongxiao Li contributed equally to this study.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionsupporting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

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Mutations inFASTKD2are associated with mitochondrial disease with multi‐OXPHOS deficiency

Wei

et al. 2020

Human Mutation

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“…Mitochondrial encephalomyopathy with developmental delay, hemiplegia, convulsions, asymmetrical brain atrophy, and low cytochrome c oxidase (COX) activity in skeletal muscle were reported in patients with mutations in FASTKD2 , encoding the fas activated serine-threonine kinase domain 2 protein [ 20 ]. FASTKD2 has a role in the assembly of the large ribosomal subunit and is required for 16S rRNA stability [ 26 , 27 ].…”

Section: Maturation Of the Primary Transcript: Mrna Processing And Stmentioning

confidence: 99%

Mitochondrial DNA transcription and translation: clinical syndromes

Boczonadi

Ricci

Horvath

2018

Essays in Biochemistry

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Diagnosing primary mitochondrial diseases is challenging in clinical practice. Although, defective oxidative phosphorylation (OXPHOS) is the common final pathway, it is unknown why different mtDNA or nuclear mutations result in largely heterogeneous and often tissue -specific clinical presentations. Mitochondrial tRNA (mt-tRNA) mutations are frequent causes of mitochondrial diseases both in children and adults. However numerous nuclear mutations involved in mitochondrial protein synthesis affecting ubiquitously expressed genes have been reported in association with very tissue specific clinical manifestations suggesting that there are so far unknown factors determining the tissue specificity in mitochondrial translation. Most of these gene defects result in histological abnormalities and multiple respiratory chain defects in the affected organs. The clinical phenotypes are usually early-onset, severe, and often fatal, implying the importance of mitochondrial translation from birth. However, some rare, reversible infantile mitochondrial diseases are caused by very specific defects of mitochondrial translation. An unbiased genetic approach (whole exome sequencing, RNA sequencing) combined with proteomics and functional studies revealed novel factors involved in mitochondrial translation which contribute to the clinical manifestation and recovery in these rare reversible mitochondrial conditions.

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“…Genome-wide linkage analysis led to the identification of a homozygous nonsense mutation in FASTKD2 gene in two siblings affected with mitochondrial encephalomyopathy associated with developmental delay, hemiplegia, convulsions and low cytochrome C oxidase activity in skeletal muscle ( 18 ). A second report recently identified FASTKD2 compound heterozygous mutations in a patient with adult-onset MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes)-like syndrome ( 27 ). These are to date the only pathogenic mutations described in a member of the FASTK family.…”

Section: Regulation Of Mitochondrial Rna Biology By the Fastk Familymentioning

confidence: 99%

The FASTK family of proteins: emerging regulators of mitochondrial RNA biology

Jourdain

Popow

Fuente

et al. 2017

Nucleic Acids Research

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The FASTK family proteins have recently emerged as key post-transcriptional regulators of mitochondrial gene expression. FASTK, the founding member and its homologs FASTKD1–5 are architecturally related RNA-binding proteins, each having a different function in the regulation of mitochondrial RNA biology, from mRNA processing and maturation to ribosome assembly and translation. In this review, we outline the structure, evolution and function of these FASTK proteins and discuss the individual role that each has in mitochondrial RNA biology. In addition, we highlight the aspects of FASTK research that still require more attention.

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Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome

Cited by 42 publications

References 19 publications

Mutations inFASTKD2are associated with mitochondrial disease with multi‐OXPHOS deficiency

Mutations inFASTKD2are associated with mitochondrial disease with multi‐OXPHOS deficiency

Mitochondrial DNA transcription and translation: clinical syndromes

The FASTK family of proteins: emerging regulators of mitochondrial RNA biology

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