Mutations inFASTKD2are associated with mitochondrial disease with multi‐OXPHOS deficiency
Xiujuan WeiMiaomiao DuDongxiao LiShumeng WenJie XieYuanyuan LiAolong ChenKun ZhangPu XuManli JiaChaowei WenHuaibin ZhouJianxin LyuYanling YangHezhi Fang
30
Citation
25
Reference
10
Related Paper
Citation Trend
Abstract:
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.Keywords:
Heteroplasmy
Mitochondrial encephalomyopathy
Mitochondrial disease
Mitochondrial diseases (MD) represent a heterogeneous group of multisystem disorders that affect tissues with high energetic demands such as muscle, nervous system, heart, endocrine system, etc, and are often manifested in children. They are caused either by a mutation in the maternally inherited mitochondrial genome, or by nuclear DNA mutation. Thirty-two patients (6 months to 16 years) were studied. All patients had full biochemical and haematological tests, neuroimaging studies, single-photon emission computed tomography in some patients, EEG, ECG, echocardiography. Lactate, ammonia, carnitine levels were measured. A molecular analysis of mitochondrial DNA was also performed by sequence. In 23 of the children MD was confirmed, in others, still not determined. Epilepsy was observed in nine patients, in combination with dilated cardiomyopathy in two children. Dilated cardiomyopathy was found in nine patients, in three patients in combination with stroke. Two paediatric patients had stroke as the first symptom of MD. Ataxia, myoclonus, lethargy, migraine, myopathy, ptosis, visual deterioration, mental delay were observed in some patients. High-frequency mutations found: A3243G, A11084G, related to the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS), also NADH 1 and 2, ATP synthase 6, cytochrome C oxidase, 16S and 12S rRNA, tRNA lysine, multiple mtDNA mutations. In our study three children with high-frequency MELAS mutation had no stroke, but epilepsy. On the contrary, in five patients with stroke no MELAS mutations were found. In conclusion, we may say that these disorders may present with a huge variety of symptoms, even if the same mutation is involved.
Mitochondrial encephalomyopathy
Mitochondrial disease
MELAS syndrome
Lactic acidosis
Myoclonic epilepsy
Cite
Citations (0)
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes) syndrome is a mitochondrial disorder characterized by myopathy, encephalopathy, lactic acidosis and stroke-like episodes.We reported a case of 14-year-old boy with no prior medical history presenting with recurrent seizures and blurring of vision. He was suspected to be a case of MELAS. In mitochondrial disease, MRI findings are non-specific or change over time, thus greatly lowering its diagnostic sensitivity. In our case, Magnetic resonance spectroscopy (MRS) was deployed in addition to traditional method of diagnostic investigations such as biochemical studies, mitochondrial DNA analysis and MRI to aid the diagnosis.
Lactic acidosis
Mitochondrial encephalomyopathy
MELAS syndrome
Mitochondrial disease
Mitochondrial Encephalomyopathies
Stroke
Cite
Citations (0)
Heteroplasmy
Mitochondrial disease
Mitochondrial encephalomyopathy
Human mitochondrial genetics
Myoclonic epilepsy
MELAS syndrome
Cite
Citations (80)
Mitochondrial respiratory chain disorders are relatively common inborn errors of energy metabolism, with a combined prevalence of one in 5000. These disorders typically affect tissues with high energy requirements, and cerebral involvement occurs frequently in childhood, often manifesting in seizures. Mitochondrial diseases are genetically heterogeneous; to date, mutations have been reported in all 37 mitochondrially encoded genes and more than 80 nuclear genes. The major genetic causes of mitochondrial epilepsy are mitochondrial DNA mutations (including those typically associated with the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS] and myoclonic epilepsy with ragged red fibres [MERRF] syndromes); mutations in POLG (classically associated with Alpers syndrome but also presenting as the mitochondrial recessive ataxia syndrome [MIRAS], spinocerebellar ataxia with epilepsy [SCAE], and myoclonus, epilepsy, myopathy, sensory ataxia [MEMSA] syndromes in older individuals) and other disorders of mitochondrial DNA maintenance; complex I deficiency; disorders of coenzyme Q(10) biosynthesis; and disorders of mitochondrial translation such as RARS2 mutations. It is not clear why some genetic defects, but not others, are particularly associated with seizures. Epilepsy may be the presenting feature of mitochondrial disease but is often part of a multisystem clinical presentation. Mitochondrial epilepsy may be very difficult to manage, and is often a poor prognostic feature. At present there are no curative treatments for mitochondrial disease. Individuals with mitochondrial epilepsy are frequently prescribed multiple anticonvulsants, and the role of vitamins and other nutritional supplements and the ketogenic diet remain unproven.
Mitochondrial disease
Mitochondrial encephalomyopathy
Myoclonic epilepsy
Lactic acidosis
MELAS syndrome
Leigh disease
Mitochondrial Encephalomyopathies
Mitochondrial respiratory chain
Ketogenic Diet
Paroxysmal dyskinesia
Cite
Citations (159)
Mitochondrial encephalomyopathy
Mitochondrial disease
Mitochondrial respiratory chain
Mitochondrial Encephalomyopathies
Cite
Citations (163)
Heteroplasmy
Mitochondrial Encephalomyopathies
Mitochondrial encephalomyopathy
Mitochondrial disease
Human mitochondrial genetics
Kearns–Sayre syndrome
Mitochondrial respiratory chain
Cite
Citations (10)
Heteroplasmy
Mitochondrial encephalomyopathy
Mitochondrial disease
Mitochondrial Encephalomyopathies
Human mitochondrial genetics
Cite
Citations (97)
Mitochondrial diseases are heterogeneous disorders, caused by mitochondrial dysfunction. Mitochondria are not regulated solely by nuclear genomic DNA but by mitochondrial DNA. It is difficult to develop effective therapies for mitochondrial disease because of the lack of mitochondrial disease models. Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the major mitochondrial diseases. The aim of this study was to generate MELAS-specific induced pluripotent stem cells (iPSCs) and to demonstrate that MELAS-iPSCs can be models for mitochondrial disease. We successfully established iPSCs from the primary MELAS-fibroblasts carrying 77.7% of m.3243A>G heteroplasmy. MELAS-iPSC lines ranged from 3.6% to 99.4% of m.3243A>G heteroplasmy levels. The enzymatic activities of mitochondrial respiratory complexes indicated that MELAS-iPSC-derived fibroblasts with high heteroplasmy levels showed a deficiency of complex I activity but MELAS-iPSC-derived fibroblasts with low heteroplasmy levels showed normal complex I activity. Our data indicate that MELAS-iPSCs can be models for MELAS but we should carefully select MELAS-iPSCs with appropriate heteroplasmy levels and respiratory functions for mitochondrial disease modeling.
Heteroplasmy
MELAS syndrome
Cite
Citations (63)
Abstract Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (OMIM:540000) is one of the most frequent mitochondrial maternal inheritance disorders. MELAS syndrome involves multiple organs, which generates a broad spectrum of manifestations, including stroke-like episodes, dementia, seizures, lactic acidaemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature. The most common mutation associated with this phenotype is m.3243A>G in the MT-TL1 gene, which encodes for a mitochondrial tRNALeu (UUR). This mutation affects mitochondrial protein translation process, transduce into protein synthesis impairment and cause deficits of essential proteins for ATP production such as transport chain complex subunits leading to impairment in energy production and multi-organ dysfunction. This lack of energy proficiency could stimulate mitochondrial growth in the smooth muscle and endothelial cells, causing angiopathy and impaired blood perfusion of several tissue and organs, leading to metabolic complications and stroke-like episodes. In this case report, we present a female patient with hearing impairment as the only manifestation, who underwent an anesthetic procedure for cerebral magnetic resonance imaging, developed metabolic acidosis and hyperlactatemia, and died. Finally, the biopsy revealed a post-mortem genetic variant for MELAS syndrome.
Lactic acidosis
Mitochondrial encephalomyopathy
Mitochondrial disease
MELAS syndrome
Angiopathy
Stroke
Cite
Citations (0)
Mitochondrial diseases are a heterogeneous group of rare genetic disorders that can be caused by mutations in nuclear (nDNA) or mitochondrial DNA (mtDNA). Mutations in mtDNA are associated with several maternally inherited genetic diseases, with mitochondrial dysfunction as a main pathological feature. These diseases, although frequently multisystemic, mainly affect organs that require large amounts of energy such as the brain and the skeletal muscle. In contrast to the difficulty of obtaining neuronal and muscle cell models, the development of induced pluripotent stem cells (iPSCs) has shed light on the study of mitochondrial diseases. However, it is still a challenge to obtain an appropriate cellular model in order to find new therapeutic options for people suffering from these diseases. In this review, we deepen the knowledge in the current models for the most studied mt-tRNA mutation-caused mitochondrial diseases, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers) syndromes, and their therapeutic management. In particular, we will discuss the development of a novel model for mitochondrial disease research that consists of induced neurons (iNs) generated by direct reprogramming of fibroblasts derived from patients suffering from MERRF syndrome. We hypothesize that iNs will be helpful for mitochondrial disease modeling, since they could mimic patient’s neuron pathophysiology and give us the opportunity to correct the alterations in one of the most affected cellular types in these disorders.
Mitochondrial encephalomyopathy
Mitochondrial disease
Mitochondrial Encephalomyopathies
Heteroplasmy
Lactic acidosis
MELAS syndrome
Myoclonic epilepsy
Reprogramming
Cite
Citations (10)