Vilma-Lotta Lehtokari

Vilma-Lotta Lehtokari
University of Helsinki | HY · Department of Medical Genetics

PhD

About

89
Publications
8,945
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
2,054
Citations

Publications

Publications (89)
Preprint
Full-text available
Introduction: Structural variants (SVs) of the nebulin gene (NEB), including intragenic duplications, deletions, and copy number variation of the triplicate region, are an established cause of recessively inherited nemaline myopathies and related neuromuscular disorders. Large deletions have been shown to cause dominantly inherited distal myopathie...
Article
Full-text available
Rare or novel missense variants in large genes such as TTN and NEB are frequent in the general population, which hampers the interpretation of putative disease-causing biallelic variants in patients with sporadic neuromuscular disorders. Often, when the first initial genetic analysis is performed, the reconstructed haplotype, i.e. phasing informati...
Article
Full-text available
Background Nemaline myopathy (NM) and related disorders (NMr) form a heterogenous group of ultra-rare (1:50,000 live births or less) congenital muscle disorders. To elucidate the self-reported physical, psychological, and social functioning in the daily lives of adult persons with congenital muscle disorders, we designed a survey using items primar...
Article
We describe three patients with asymmetric congenital myopathy without definite nemaline bodies and one patient with severe nemaline myopathy. In all four patients, the phenotype had been caused by pathogenic missense variants in ACTA1 leading to the same amino acid change, p.(Gly247Arg). The three patients with milder myopathy were mosaic for thei...
Article
Full-text available
Background: Pathogenic variants in the TPM3 gene, encoding slow skeletal muscle α-tropomyosin account for less than 5% of nemaline myopathy cases. Dominantly inherited or de novo missense variants in TPM3 are more common than recessive loss-of-function variants. The recessive variants reported to date seem to affect either the 5' or the 3' end of...
Article
Full-text available
Nemaline myopathy (NM), a structural congenital myopathy, presents a significant clinical and genetic heterogeneity. Here, we compiled molecular and clinical data of 30 Brazilian patients from 25 unrelated families. Next-generation sequencing was able to genetically classify all patients: sixteen families (64%) with mutation in NEB, five (20%) in A...
Article
Full-text available
The sarcomeric giants nebulin and titin both contain intragenic segmental duplication regions. Segmental duplication regions are prevalent throughout the genome and are known potential hotspots for recurrent copy number variation and may harbour pathogenic aberrations. Using our custom comparative genomic hybridization array, we have shown that gai...
Article
Nemaline myopathy (NM) and related disorders (NMr) are ultrarare congenital myopathies with severity varying from mild muscle- or muscle group-specific weakness to a neonatally lethal disorder. Medical and biomedical studies of NM and NMr have dominated the research field, whereas little is known about coping in everyday life among persons with NM....
Article
Full-text available
Intragenic segmental duplication regions are potential hotspots for recurrent copy number variation and possible pathogenic aberrations. Two large sarcomeric genes, nebulin and titin, both contain such segmental duplication regions. Using our custom Comparative Genomic Hybridisation array, we have previously shown that a gain or loss of more than o...
Article
Full-text available
The human genome contains repetitive regions, such as segmental duplications, known to be prone to copy number variation. Segmental duplications are highly identical and homologous sequences, posing a specific challenge for most mutation detection methods. The giant nebulin gene is expressed in skeletal muscle. It harbors a large segmental duplicat...
Preprint
Full-text available
Intragenic segmental duplication regions are potential hotspots for recurrent copy number variation and possible pathogenic aberrations. Two large sarcomeric genes, nebulin and titin, both contain such segmental duplication regions. Using our custom Comparative Genomic Hybridization array, we have previously shown that a gain or loss of more than o...
Poster
Full-text available
Segmental duplications (SD) are prone to copy number variations (CNV). SD blocks are typically highly identical sequences, posing a specific challenge for most molecular genetic methods. Nebulin (NEB) is a large structural protein of the thin filament in the sarcomere. In its mid-region, it harbors an SD of eight exons repeated three times – the tr...
Article
We report the first mosaic mutation, a deletion of exons 11-107, identified in the nebulin gene in a Finnish patient presenting with a predominantly distal congenital myopathy and asymmetric muscle weakness. The female patient is ambulant and currently 26 years old. Muscle biopsies showed myopathic features with type 1 fibre predominance, strikingl...
Poster
Full-text available
The Y-box binding protein 3 (YBX3) has been described as a transcriptional regulator and translational repressor of various proteins in skeletal and heart muscle. Its functions include, among others, the gradual repression of myogenin during myogenesis. By exome sequencing in a Finnish patient with an unusual form of nemaline myopathy, we have foun...
Article
We report the first family with a dominantly inherited mutation of the nebulin gene (NEB). This ∼100 kb in-frame deletion encompasses NEB exons 14-89, causing distal nemaline/cap myopathy in a three-generation family. It is the largest deletion characterized in NEB hitherto. The mutated allele was shown to be expressed at the mRNA level and further...
Article
Full-text available
Introduction Nebulin is a giant actin‐binding protein in the thin filament of the skeletal muscle sarcomere. Studies of nebulin interactions are limited by the size, complexity and poor solubility of the protein. We divided the nebulin super‐repeat region into a super‐repeat panel, and studied nebulin/actin interactions. Methods Actin binding was...
Article
Full-text available
Background: Our previous array, the Comparative Genomic Hybridisation design (CGH-array) for nemaline myopathy (NM), named the NM-CGH array, revealed pathogenic copy number variation (CNV) in the genes for nebulin (NEB) and tropomyosin 3 (TPM3), as well as recurrent CNVs in the segmental duplication (SD), i.e. triplicate, region of NEB (TRI, exons...
Article
We present here a Finnish nemaline myopathy family with a dominant mutation in the skeletal muscle α-actin gene, p.(Glu85Lys), segregating in three generations. The index patient, a 5-year-old boy, had the typical form of nemaline myopathy with congenital muscle weakness and motor milestones delayed but reached, while his mother never had sought me...
Poster
Full-text available
Nemaline myopathy (NM) is caused by mutations in at least eleven different genes, but most commonly by recessive mutations in the nebulin gene (NEB), a 183 exon gene essential for correct sarcomere structure and function. NEB harbors a 32kb triplicate region (TRI), in which eight exons are usually repeated three times (ex 82-89, 90-97, 98-105). We...
Poster
Full-text available
Functional studies of YBX3 variants associated with nemaline myopathy
Article
Objective: Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important de...
Article
Full-text available
Background and Objectives Nemaline myopathy may be caused by pathogenic variants in the TPM3 gene and is then called NEM1. All previously identified disease-causing variants are point mutations including missense, nonsense and splice-site variants. The aim of the study was to identify the disease-causing gene in this patient and verify the NM diagn...
Article
Recently, new large variants have been identified in the nebulin gene (NEB) causing nemaline myopathy (NM). NM constitutes a heterogeneous group of disorders among the congenital myopathies, and disease-causing variants in NEB are a main cause of the recessively inherited form of NM. NEB consists of 183 exons and it includes homologous sequences su...
Article
Journal of Human Genetics, official journal of the Japan Society of Human Genetics, publishes original articles and reviews on all aspects of human genetics, including medical genetics and genomics
Article
A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB ar...
Conference Paper
Recently, new large mutations have been identified in the nebulin gene (NEB) causing nemaline myopathy (NM). NM constitutes a heterogeneous group of disorders among the congenital myopathies, and mutations in NEB are a main cause of the recessively inherited form. NEB consists of 183 exons and it includes a 32 kb triplicate region (TRI) where eight...
Conference Paper
Using our self-designed NM-CGH microarray, which we have developed to identify large copy number variations in the currently known nine nemaline myopathy (NM) genes, we identified the first large (>20 kb) aberration in the alpha-tropomyosin gene (TPM3). This homozygous mutation deletes the promoter as well as the muscle- specific exons 1 and 2 of T...
Conference Paper
Mutation analysis of the known nemaline myopathy (NM)-causing genes in a Finnish patient with an unusual form of NM, with legs clearly stronger than arms, did not reveal the cause of the disease. A heterozygous TPM3 splice site mutation, delTAGG, in intron 1 was identified, inherited from the healthy father. The mutation was predicted to be recessi...
Conference Paper
Nemaline myopathy (NM) is a disorder of the skeletal muscle thin filament characterised by muscle dysfunction and electron-dense protein accumulations (nemaline bodies). Pathogenic mutations have been described in nine genes to date, but the genetic basis remains unknown in many cases. We used whole exome sequencing (WES) in two families with NM an...
Conference Paper
Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy (NM), cap myopathy, core-rod myopathy, congenital fibre-type disproportion, core-rod myopathy, distal arthrogryposes and Escobar syndrome. Here we correlate the clinical picture of these diseases with novel (16) and previously reported (31) mutations o...
Article
Full-text available
Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sang...
Article
Full-text available
Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We underto...
Article
Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy (NM), cap myopathy, core-rod myopathy, congenital fibre-type disproportion, distal arthrogryposes and Escobar syndrome. We correlate the clinical picture of these diseases with novel (16) and previously reported (31) mutations of the TPM2 and TPM3 gene...
Article
Nemaline myopathy (NM) is a congenital disorder associating muscle weakness with rods in muscle biopsy. Clinical presentation is variable spanning from severe to mild forms. Seven genes are associated with NM. The nebulin (NEB) gene is the most commonly mutated accounting for 50% of cases. We performed a muscle morphological analysis of thirteen NE...
Article
One of the key components in stabilizing and determining the lengths of the actin filaments of the skeletal muscle sarcomere and in the neurons of the brain is the gigantic protein nebulin. Its size varies from 600 to 900 kDa and correlates with the length of the actin filaments. A huge variation in length is produced by differential usage of the a...
Article
Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targete...
Article
Full-text available
Mutations in the TPM2 gene, which encodes β-tropomyosin, are an established cause of several congenital skeletal myopathies and distal arthrogryposis. We have identified a TPM2 mutation, p.K7del, in five unrelated families with nemaline myopathy and a consistent distinctive clinical phenotype. Patients develop large joint contractures during childh...
Article
Full-text available
Nemaline myopathy (NM) constitutes a heterogeneous group of disorders among the congenital myopathies. Mutations in the nebulin gene (NEB) are a main cause of recessively inherited NM. Sixty-eight different mutations causing NM have been published in NEB to date. Almost all are point mutations or small deletions. The only large mutation described i...
Article
Published case reports of mutations in the tropomyosin genes describe a variety of neuromuscular disorders. The tropomyosins (Tms) exist as coiled-coil homo- or heterodimers forming head-to-tail polymers, running along the length of the actin molecule. They are encoded by four different genes; αTm (TPM1), βTm (TPM2), γTm (TPM3), and δTm (TPM4), gen...
Article
Nebulin is one of the main components of the thin filament of the muscle sarcomere and the gene encoding nebulin (NEB) is, with its 183 exons, one of the biggest genes in the human genome. Mutations in NEB are the most common cause of autosomal recessive nemaline myopathy (NM), which is diagnosed on the basis of muscle weakness and protein aggregat...
Conference Paper
Full-text available
Two mutations, skeletal α-actin K326N and β-tropomyosin ΔK7 were reported in patients with ‘stiff’ muscles and spontaneous contractures, respectively, suggesting a hypercontractile phenotype. K326N actin was isolated from a patient biopsy and ΔK7 β-tropomyosin was expressed in baculovirus/sf9 cells. Ca2+ regulation of reconstituted thin filaments w...
Article
Full-text available
Nemaline myopathy (NM) constitutes a heterogeneous group of congenital myopathies. Mutations in the nebulin gene (NEB) are the main cause of recessively inherited NM. NEB is one of the most largest genes in human. To date, 68 NEB mutations, mainly small deletions or point mutations have been published. The only large mutation characterized is the 2...
Article
Nemaline myopathy, also called rod myopathy, is a relatively common congenital myopathy and probably second in incidence only to central core disease. The mainstay of diagnosis is histopathology, but detection of the causative mutation is mandatory for determining the mode of inheritance and for prenatal diagnosis. The authors report two siblings w...
Article
To increase awareness to the possibility of nemaline myopathy (NM) when abnormal prenatal ultrasound findings appear together with a carrier state for the common exon 55 deletion in the nebulin gene (NEB) of an Ashkenazi Jewish parent. We describe four unrelated pregnancies with abnormal prenatal ultrasound findings resulting in the birth of newbor...
Article
Introduction Les myopathies distales (MD) constituent un groupe de myopathies génétiques rares et hétérogènes caractérisées par une faiblesse progressive de début distal et dont les explorations suggèrent un processus myopathique. La dystrophie myotonique de Steinert et la dystrophie musculaire facio-scapulo-humérale sont exclues de ce groupe. La c...
Article
Mutations in the nebulin gene are the main cause of autosomal recessive nemaline myopathy, with clinical presentations ranging from mild to severe disease. We have previously reported a nonspecific distal myopathy caused by homozygous missense mutations in the nebulin gene in six Finnish patients from four different families. Here we describe three...
Article
Full-text available
Nemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50% of cases. We describe two siblings with severe NM, arthrog...
Article
Full-text available
Nebulin is a giant protein expressed at high levels in skeletal muscle. Mutations in the nebulin gene (NEB) lead to muscle weakness and various congenital myopathies. Despite increasing clinical and scientific interest, the pathogenesis of weakness remains unknown. The present study, therefore, aims at unraveling the underlying molecular mechanisms...
Article
In 2004, Anderson et al. reported a homozygous 2502 bp deletion including exon 55 of the nebulin gene in five Ashkenazi Jewish probands with nemaline myopathy. We determined the occurrence of this deletion in a world-wide series of 355 nemaline myopathy probands with no previously known mutation in other genes and found the mutation in 14 probands,...
Article
Nemaline myopathy is a heterogenous form of congenital myopathy characterised by a variable spectrum of clinical features, predominated in the severe form by profound muscle hypotonia and weakness accompanied by respiratory insufficiency. The clinical variability, with differing age of onset and severity of symptoms makes the diagnosis of nemaline...
Article
Full-text available
To date, six genes are known to cause nemaline (rod) myopathy (NM), a rare congenital neuromuscular disorder. In an attempt to find a seventh gene, we performed linkage and subsequent sequence analyses in 12 Turkish families with recessive NM. We found homozygosity in two of the families at 1q12-21.2, a region encompassing the gamma-tropomyosin gen...
Article
Full-text available
We describe a novel, recessively inherited distal myopathy caused by homozygous missense mutations in the nebulin gene (NEB), in which other combinations of mutations are known to cause nemaline (rod) myopathy (NM). Two different missense mutations were identified in homozygous form in seven Finnish patients from four unrelated families with childh...
Article
"Cap myopathy" or "cap disease" is a congenital myopathy characterised by cap-like structures at the periphery of muscle fibres, consisting of disarranged thin filaments with enlarged Z discs. Here we report a deletion in the beta-tropomyosin (TPM2) gene causing cap disease in a 36-year-old male patient with congenital muscle weakness, myopathic fa...
Article
Nemaline myopathy (NM) is a congenital myopathy characterized by muscle weakness and nemaline bodies in affected myofibers. Five NM genes, all encoding components of the sarcomeric thin filament, are known. We report identification of a sixth gene, CFL2, encoding the actin-binding protein muscle cofilin-2, which is mutated in two siblings with cong...
Article
Full-text available
Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder of skeletal muscle caused by mutations in at least five different genes encoding thin filament proteins of the striated muscle sarcomere. We have previously described 18 different mutations in the last 42 exons of the nebulin gene (NEB) in 18 families with NM. Here we rep...