Katarina Pelin

• Ph.D.
• Lecturer at University of Helsinki

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...

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...

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...

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...

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...

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...

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...

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...

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...

The congenital myopathies are a heterogeneous group of skeletal muscle disorders characterised by muscle weakness present at birth and typical abnormalities in skeletal muscle fibres, such as protein aggregates, centrally located nuclei or areas lacking mitochondria. Mutations in more than 30 different genes can cause a congenital myopathy. The inh...

Gohlke et al. show the importance of nebulin size for optimal skeletal muscle function in animals of different body size.

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...

Nemaline myopathies are a clinically and genetically heterogeneous group of congenital myopathies, mainly characterized by muscle weakness, hypotonia and respiratory insufficiency. Here, we report a male foetus of consanguineous parents with a severe congenital syndrome characterized by arthrogryposis detected at 13 weeks of gestation. We describe...

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...

Abstract Nemaline myopathy (NM) caused by mutations in the gene encoding nebulin (NEB) accounts for at least 50% of all NM cases worldwide, representing a significant disease burden. Most NEB-NM patients have autosomal recessive disease due to a compound heterozygous genotype. Of the few murine models developed for NEB-NM, most are Neb knockout mod...

The congenital myopathies form a large clinically and genetically heterogeneous group of disorders. Currently mutations in at least 27 different genes have been reported to cause a congenital myopathy, but the number is expected to increase due to the accelerated use of next-generation sequencing methods. There is substantial overlap between the ca...

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...

Nebulin is a very large protein required for assembly of the contractile machinery in muscle. Mutations in the nebulin gene NEB are a common cause of nemaline myopathy. Nebulin mRNA is alternatively-spliced so that each mRNA contains either exon 143 or exon 144. We have produced monoclonal antibodies specific for the regions of nebulin encoded by t...

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...

Objective: Copy number variants (CNVs) were analyzed from next-generation sequencing data, with the aim of improving diagnostic yield in skeletal muscle disorder cases. Methods: Four publicly available bioinformatic analytic tools were used to analyze CNVs from sequencing data from patients with muscle diseases. The patients were previously analyz...

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...

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...

Functional studies of YBX3 variants associated with nemaline myopathy

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...

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...

Despite the expression of the mutated gene in all muscles, selective muscles are involved in genetic muscular dystrophies. Different muscular dystrophies show characteristic patterns of fatty degenerative changes by muscle imaging, even to the extent that the patterns have been used for diagnostic purposes. However, the underlying molecular mechani...

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...

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

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...

Mutations in the gene encoding β‐tropomyosin, TPM2 , cause clinically and histologically overlapping congenital myopathies such as nemaline myopathy, cap myopathy and core‐rod myopathy, and often also a fibre size disproportion between type 1 and type 2 muscle fibres. In addition, TPM2 mutations can cause distal arthrogryposis and Escobar syndrome,...

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...

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...

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...

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...

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...

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...

Background Nemaline myopathy (NM) is a rare genetic muscle disorder, but one of the most common among the congenital myopathies. NM is caused by mutations in at least nine genes: Nebulin (NEB), α-actin (ACTA1), α-tropomyosin (TPM3), β-tropomyosin (TPM2), troponin T (TNNT1), cofilin-2 (CFL2), Kelch repeat and BTB (POZ) domain-containing 13 (KBTBD13)...

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...

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...

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...

The nebulin gene (NEB) has 183 exons encoding transcripts up to 26 kb in length. Mutations found in NEB are dispersed throughout the gene. Mutations cause autosomal recessive nemaline myopathy, distal myopathy and core-rod myopathy, for which no therapy is available. The size of NEB limits the options of gene therapy development. Thus, our research...

Nebulin is a large actin-binding protein of the skeletal muscle sarcomere. Multiple isoforms of nebulin are produced from the 183-exon-containing nebulin gene (NEB). Mutations in NEB cause nemaline myopathy, distal myopathy, and core-rod myopathy. Nebulin mRNA expression was assessed by microarrays and RT-PCR in 21 human leg muscle and 2 brain samp...

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...

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...

The nebulin gene (NEB) has 183 exons encoding transcripts up to 26 kb in length. Mutations found in NEB are dispersed throughout the gene, i.e. no mutational hot spots are evident. Mutations cause autosomal recessive nemaline myopathy, distal nebulin myopathy and core-rod myopathy, for which no therapy is available. The size of NEB limits the optio...

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...

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...

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...

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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,...

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...

Nebulin is an enormous protein of the muscle sarcomere. It is a determinant of thin filament length, Z-disk structure and fiber contractility. The nebulin gene contains four regions of alternative splicing, providing a wealth of different isoforms of the protein. The precise function of these numerous isoforms in various types of muscle tissue rema...

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...

"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...

The human nebulin gene includes 183 exons and four regions of alternative splicing. The mouse nebulin gene, with 166 exons, has a similar organization. Here we describe the expression patterns of one of the alternatively spliced regions of nebulin: exons 127 and 128 in the mouse gene, corresponding to human nebulin exons 143 and 144. Expression was...

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...

We report muscle MRI findings of 10 patients from 8 families with nemaline myopathy. Patients with involvement of the nebulin (NEB) gene showed a consistent pattern of selective muscle involvement corresponding to clinical severity. In mild cases, there was complete sparing of thigh muscles and selective involvement of tibialis anterior and soleus....

We present comparisons of the clinical pictures in a series of 60 patients with nemaline myopathy in whom mutations had been identified in the genes for nebulin or skeletal muscle alpha-actin. In the patients with nebulin mutations, the typical form of nemaline myopathy predominated, while severe, mild or intermediate forms were less frequent. Auto...

The giant nebulin protein is a fundamental structural component of the thin filaments of the striated muscle sarcomere. Nebulin binds to actin and the size of nebulin correlates with actin filament length, suggesting that nebulin may determine the length of the thin filaments during myofibrillogenesis. We have previously described the genomic organ...