A5023082449- Hereditary Neurological Disorders
- Mitochondrial Function and Pathology
- Neurological diseases and metabolism
- Neurogenetic and Muscular Disorders Research
- Genetic Neurodegenerative Diseases
- Metabolism and Genetic Disorders
- Muscle Physiology and Disorders
- RNA Research and Splicing
- Endoplasmic Reticulum Stress and Disease
- Cardiomyopathy and Myosin Studies
- RNA modifications and cancer
- Toxin Mechanisms and Immunotoxins
- Amyotrophic Lateral Sclerosis Research
- ATP Synthase and ATPases Research
- Cardiovascular Effects of Exercise
- Glycogen Storage Diseases and Myoclonus
- CRISPR and Genetic Engineering
- Lysosomal Storage Disorders Research
- Genetics and Neurodevelopmental Disorders
- Cellular Mechanics and Interactions
- Ubiquitin and proteasome pathways
- Cellular transport and secretion
- Cell Adhesion Molecules Research
- Signaling Pathways in Disease
- RNA regulation and disease
University of Helsinki
2016-2025
Helsinki University Hospital
2015-2025
Finnish Society of Sciences and Letters
2024
Tampere University
2005-2018
Tampere University Hospital
2005-2018
Institute for Molecular Medicine Finland
2015-2018
Neurosciences Institute
2018
Institute for Stem Cell Biology and Regenerative Medicine
2018
University of Pennsylvania
2018
Helsinki Art Museum
2017
Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations which cause adult-onset progressive external ophthalmoplegia (PEO) multiple deletions. We generated transgenic mice expressing mouse PEO patient mutations. Multiple deletions accumulate in tissues these mice, resulting respiratory dysfunction chronic late-onset disease starting at...
Mitochondria are essential organelles with multiple functions, the most well known being production of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). The mitochondrial diseases defined by impairment OXPHOS. They a diverse group that can present in virtually any tissue either adults or children. Here we review main molecular mechanisms diseases, as presently known. A number disease-causing genetic defects, nuclear genome mitochondria's own genome, DNA (mtDNA), have...
Mitochondrial DNA (mtDNA) is an essential multicopy genome, compacted into protein-DNA clusters called nucleoids. Maintaining adequate mtDNA copy number crucial for cellular viability. Loss of results in severe human syndromes, whereas increased has been suggested to improve survival from myocardial infarction mice and be a promising therapeutic strategy mitochondrial disease. The mechanisms that regulate amount organization are, however, not fully understood. Of the proteins required...
Neurofilament light (NFL) is one of the proteins forming multimeric neuron-specific intermediate filaments, neurofilaments, which fill axonal cytoplasm, establish caliber growth, and provide structural support. Dominant missense mutations recessive nonsense in neurofilament gene (
De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified dominantly inherited heterozygous variant c.1064G > A (p.G355D) mother presenting hereditary spastic paraplegia (HSP) neuropathy her son dyskinetic cerebral palsy, both disease onset childhood. HSP is...
Inherited peripheral neuropathies are a heterogeneous group of disorders that can affect patients all ages. Children with inherited neuropathy often develop severe disability, but the genetic causes recessive early-onset axonal not fully known. We have taken whole-exome sequencing approach to identify causative disease mutations in single neuropathy. Here, we report compound heterozygous tripartite motif containing 2 (TRIM2) gene patient childhood-onset neuropathy, low weight and small...
<h3>Objective:</h3> We describe the phenotype consistent with axonal Charcot-Marie-Tooth disease type 2 (CMT2) in 4 families a c.197G>T (p.(Gly66Val)) variant <i>CHCHD10</i>. <h3>Methods:</h3> sequenced <i>CHCHD10</i> gene cohort of 107 CMT2 unknown etiology. The patients were characterized by clinical examination and electroneuromyography. Muscle MRI biopsy muscle or nerve performed selected cases. Neuropathologic autopsy was 1 case. <h3>Results:</h3> found 6 families, which included...
We aimed to decipher the molecular genetic basis of disease in a cohort children with uniform clinical presentation neonatal irritability, spastic or dystonic quadriplegia, virtually absent psychomotor development, axonal neuropathy, and elevated blood/CSF lactate.We performed whole-exome sequencing blood DNA from index patients. Detected compound heterozygous mutations were confirmed by Sanger sequencing. Structural predictions bacterial activity assay evaluate functional consequences...
Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started shed light on essential roles each receptor different tissues cell types. Variants ITPR3 gene, which encodes IP3R3, have recently been found cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J). In...
Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations gene MCM3AP, encoding germinal center associated nuclear protein (GANP), nine affected individuals five unrelated families. The variants were with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild moderate intellectual disability was present seven of individuals. either compound heterozygous homozygous...
Clinical diagnostics in adults with hereditary neurological diseases is complicated by clinical and genetic heterogeneity, as well lifestyle effects. Here, we evaluate the effectiveness of exome sequencing costs our difficult-to-diagnose adult patient cohort. Additionally, expand phenotypic spectrum disorders Finland.We performed (CES) to 100 patients from Finland symptoms suspected cause. The were classified myopathy (n = 57), peripheral neuropathy 16), ataxia 15), spastic paraplegia 4),...
<h3>Objective</h3> We used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light (<i>NEFL</i>) underlying early-onset Charcot-Marie-Tooth (CMT) disease. <h3>Methods</h3> Motor neurons were differentiated from induced pluripotent stem cells a patient with CMT carrying novel homozygous mutation <i>NEFL</i>. Quantitative PCR, protein analytics, immunocytochemistry, electron microscopy, and single-cell...
Mitochondrial intermembrane space proteins CHCHD2 and CHCHD10 have roles in motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy axonal neuropathy Parkinson's disease. They form a complex of unknown function. Here we address the importance these two human neurons. We show that gene edited induced pluripotent stem cells (iPSC) lacking either or are viable can be differentiated into functional neurons fire spontaneous evoked action potentials. Mitochondria...
Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic amenable to a specific mechanism-based treatment, as L-serine supplementation can used lower neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause neurodegeneration. The treatment is so far untested in HSAN1C caused by variants serine palmitoyl transferase subunit 2 (SPTLC2) gene. aim this study was establish whether oral lowers 1-deoxySL patient with HSAN1C, perform dose escalation find minimal effective dose,...
Abstract Objective ITPR3 , encoding inositol 1,4,5‐trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot‐Marie‐Tooth neuropathy. Here, we present genetic and functional evidence that is gene. Methods Whole‐exome sequencing of four affected individuals in an autosomal dominant family one individual who the only his used to identify disease‐causing variants. Skin fibroblasts from two were analyzed functionally by western blotting, quantitative...
HSPB1 belongs to the family of small heat shock proteins (sHSP) that have importance in protection against unfolded protein stress, cancer cells for escaping drug toxicity stress and neurons suppression aggregates. sHSPs a conserved α-crystalline domain (ACD), flanked by variable N- C-termini, whose functions are not fully understood. Dominant missense variants HSPB1, locating mostly ACD, been linked inherited neuropathy.Patients underwent detailed clinical neurophysiologic characterization....
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are ER Ca2+-release channels that control a broad set of cellular processes. Animal models lacking IP3Rs in different combinations display severe developmental phenotypes. Given the importance human diseases, we investigated their role induced pluripotent stem cells (hiPSC) by developing single IP3R and triple knockouts (TKO). Genome edited TKO-hiPSC all three isoforms, IP3R1, IP3R2, IP3R3, failed to generate Ca2+ signals response agonists...
Ribonucleotide reductase (RNR) is the rate-limiting enzyme in deoxyribonucleoside triphosphate (dNTP) biosynthesis, with important roles nuclear genome maintenance. RNR also essential for maintenance of mitochondrial DNA (mtDNA) mammals. The mechanisms regulating mtDNA copy number mammals are only being discovered. In budding yeast, overexpression resulted increased levels, and rescued disease phenotypes caused by a mutant polymerase. This raised question whether increase induction could be...
Objectives Mutations in the CHCHD10 gene, which encodes a mitochondrially targeted protein, have emerged as an important cause of motor neuron disease and frontotemporal lobar degeneration. The aim this study was to assess clinical variability large family carrying p.Gly66Val mutation gene. This has recently been reported late-onset spinal muscular atrophy (SMAJ) or sensorimotor axonal Charcot–Marie–Tooth neuropathy (CMT2) Finnish population. Materials methods Nine affected members extended...
Motor neuron disorders (MNDs) are a heterogeneous group of diseases that result from degeneration motor neurons. If both upper and lower neurons (UMNs LMNs) affected, the disease is classified as amyotrophic lateral sclerosis (ALS). Primary (PLS) progressive muscular atrophy (PMA) selectively affect UMNs or LMNs, respectively, but sometimes considered to be incomplete ALS variants because their phenotype may evolve into typical over time. Bulbar affection in UMN would favour diagnosis PLS...