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1.
Mov Disord ; 38(12): 2217-2229, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37752895

ABSTRACT

BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient. CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Subject(s)
Dystonic Disorders , Hyponatremia , Leigh Disease , Movement Disorders , Child, Preschool , Humans , Dystonic Disorders/complications , Hyponatremia/complications , Leigh Disease/genetics , Leigh Disease/complications , Methyltransferases/genetics , Mitochondrial Proteins/genetics , Movement Disorders/complications , Mutation/genetics , Child , Young Adult
2.
Stem Cell Res ; 76: 103379, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38458030

ABSTRACT

Leigh syndrome is a rare autosomal recessive disorder showcasing a diverse range of neurological symptoms. Classical Leigh syndrome is associated with mitochondrial complex I deficiency, primarily resulting from biallelic mutations in the NDUFAF5 gene, encoding the NADH:ubiquinone oxidoreductase complex assembly factor 5. Using the Sendai virus delivery system, we generated an induced pluripotent stem cell line from peripheral blood mononuclear cells of a 47-years-old female patient who carried a homozygous NDUFAF5 c.836 T > G (p.Met279Arg) mutation. This cellular model serves as a tool for investigating the underlying pathogenic mechanisms and for the development of potential treatments for Leigh syndrome.


Subject(s)
Induced Pluripotent Stem Cells , Leigh Disease , Mitochondrial Diseases , Humans , Female , Middle Aged , Leigh Disease/genetics , Mutation, Missense , Induced Pluripotent Stem Cells/pathology , Leukocytes, Mononuclear/pathology , Mitochondrial Diseases/genetics , Mitochondrial Diseases/pathology , Mutation , Methyltransferases/genetics , Mitochondrial Proteins/genetics
3.
Stem Cell Res ; 63: 102856, 2022 08.
Article in English | MEDLINE | ID: mdl-35868289

ABSTRACT

Aceruloplasminemia is a rare autosomal recessive disorder caused by mutations in the CP gene, encoding the copper-binding protein ceruloplasmin. A mutation in the CP gene results in brain and systemic iron overload, which is classified as a rare subtype of neurodegeneration with brain iron accumulation (NBIA). Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells from peripheral blood mononuclear cells of a patient carrying the CP c.607+1 delG homozygous splicing mutation. The generated cell line retained the original genotype, expressed pluripotency markers, and differentiated into cells of the three germ layers.


Subject(s)
Cell Line , Ceruloplasmin , Induced Pluripotent Stem Cells , Ceruloplasmin/deficiency , Ceruloplasmin/genetics , Humans , Iron Metabolism Disorders , Leukocytes, Mononuclear , Mutation , Neurodegenerative Diseases
4.
Stem Cell Res ; 51: 102190, 2021 03.
Article in English | MEDLINE | ID: mdl-33517123

ABSTRACT

Neurodegeneration with brain iron accumulation (NBIA) is a genetically and phenotypically heterogeneous group of inherited neurodegenerative disorder characterized by basal ganglia iron deposition. Mutations in Pantothenate Kinase 2 (PANK2) are major genetic causes for patients with NBIA. The location of PANK2 in the mitochondria suggests mutant PANK2 causing mitochondrial dysfunction in the pathogenesis of NBIA. Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a female patient having compound heterozygous mutations in PANK2. This cellular model could provide a platform for pathophysiological studies of NBIA in the future.


Subject(s)
Induced Pluripotent Stem Cells , Pantothenate Kinase-Associated Neurodegeneration , Brain/diagnostic imaging , Female , Humans , Iron Metabolism Disorders , Leukocytes, Mononuclear , Mutation , Neuroaxonal Dystrophies , Phosphotransferases (Alcohol Group Acceptor)/genetics
5.
Stem Cell Res Ther ; 12(1): 508, 2021 09 22.
Article in English | MEDLINE | ID: mdl-34551822

ABSTRACT

BACKGROUND: The c.G6055A (p.G2019S) mutation in leucine-rich repeat kinase 2 (LRRK2) is the most prevalent genetic cause of Parkinson's disease (PD). CRISPR/Cas9-mediated genome editing by homology-directed repair (HDR) has been applied to correct the mutation but may create small insertions and deletions (indels) due to double-strand DNA breaks. Adenine base editors (ABEs) could convert targeted A·T to G·C in genomic DNA without double-strand breaks. However, the correction efficiency of ABE in LRRK2 c.G6055A (p.G2019S) mutation remains unknown yet. This study aimed to compare the mutation correction efficiencies and off-target effects between HDR and ABEs in induced pluripotent stem cells (iPSCs) carrying LRRK2 c.G6055A (p.G2019S) mutation. METHODS: A set of mutation-corrected isogenic lines by editing the LRRK2 c.G6055A (p.G2019S) mutation in a PD patient-derived iPSC line using HDR or ABE were established. The mutation correction efficacies, off-target effects, and indels between HDR and ABE were compared. Comparative transcriptomic and proteomic analyses between the LRRK2 p.G2019S iPSCs and isogenic control cells were performed to identify novel molecular targets involved in LRRK2-parkinsonism pathways. RESULTS: ABE had a higher correction rate (13/53 clones, 24.5%) than HDR (3/47 clones, 6.4%). Twenty-seven HDR clones (57.4%), but no ABE clones, had deletions, though 14 ABE clones (26.4%) had off-target mutations. The corrected isogenic iPSC-derived dopaminergic neurons exhibited reduced LRRK2 kinase activity, decreased phospho-α-synuclein expression, and mitigated neurite shrinkage and apoptosis. Comparative transcriptomic and proteomic analysis identified different gene expression patterns in energy metabolism, protein degradation, and peroxisome proliferator-activated receptor pathways between the mutant and isogenic control cells. CONCLUSIONS: The results of this study envision that ABE could directly correct the pathogenic mutation in iPSCs for reversing disease-related phenotypes in neuropathology and exploring novel pathophysiological targets in PD.


Subject(s)
Induced Pluripotent Stem Cells , Parkinson Disease , Dopaminergic Neurons , Gene Editing , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Mutation , Parkinson Disease/genetics , Parkinson Disease/therapy , Phenotype , Proteomics
6.
Stem Cell Res ; 49: 102032, 2020 12.
Article in English | MEDLINE | ID: mdl-33068888

ABSTRACT

Mutations in an open-reading frame on chromosome 19 (C19orf12) were identified as one of the causative genes for neurodegeneration with brain iron accumulation (NBIA). Because of the mitochondrial localization of the derived protein, this variant is referred to as mitochondrial membrane protein-associated neurodegeneration with brain iron accumulation (MPAN). Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a female patient with MPAN having a novel heterozygous frameshift mutation caused by an insertion, c.273_274insA (p.P92Tfs*9), in C19orf12. This cellular model could provide a platform for pathophysiological studies of MPAN.


Subject(s)
Induced Pluripotent Stem Cells , Neurodegenerative Diseases , Brain , Female , Frameshift Mutation/genetics , Humans , Iron Metabolism Disorders , Leukocytes, Mononuclear , Mitochondrial Proteins/genetics , Mutation , Neuroaxonal Dystrophies
7.
Stem Cell Res ; 49: 102031, 2020 12.
Article in English | MEDLINE | ID: mdl-33070102

ABSTRACT

A novel missense mutation, c.941A > C (p.Y314S), in mitochondrial ubiquinol-cytochrome c reductase core protein I (UQCRC1) gene, was recently identified in a family with autosomal-dominant late-onset parkinsonism and polyneuropathy. UQCRC1 encodes a mitochondria respiratory complex III protein. Mutant UQCRC1 cells showed decreased mitochondrial activity and neurite degeneration. Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a male patient having a heterozygous UQCRC1 p.Y314S mutation. The established iPSCs could differentiate into three germ layers in vivo. This cellular model provides a platform for further studies of UQCRC1-related parkinsonism and polyneuropathy.


Subject(s)
Induced Pluripotent Stem Cells , Parkinsonian Disorders , Polyneuropathies , Humans , Leukocytes, Mononuclear , Male , Mutation , Parkinsonian Disorders/genetics
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