Mathias Gautel
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View article: A comprehensive framework for the interpretation of TTN missense variants
A comprehensive framework for the interpretation of TTN missense variants Open
Background: Missense variants in TTN pose a major challenge in genetic diagnostics due to their high frequency in the general population, the large size of the gene, and the complex multidomain architecture of the titin protein. While the …
View article: The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes
The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes Open
Protein homeostasis is crucial for maintaining cardiomyocyte (CM) function. Disruption of proteostasis results in accumulation of protein aggregates causing cardiac pathologies such as hypertrophy, dilated cardiomyopathy (DCM), and heart f…
View article: TITINdb2—expanding annotation and structural information for protein variants in the giant sarcomeric protein titin
TITINdb2—expanding annotation and structural information for protein variants in the giant sarcomeric protein titin Open
Summary We present TITINdb2, an update to the TITINdb database previously constructed to facilitate the identification of pathogenic missense variants in the giant protein titin, which are associated with a variety of skeletal and cardiac …
View article: Inferring disease course from differential exon usage in the wide titinopathy spectrum
Inferring disease course from differential exon usage in the wide titinopathy spectrum Open
Objective Biallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult‐onset limb‐girdle muscular dystrophy, with or witho…
View article: A Proof of Principle 2D Spatial Proteome Mapping Analysis Reveals Distinct Regional Differences in the Cardiac Proteome
A Proof of Principle 2D Spatial Proteome Mapping Analysis Reveals Distinct Regional Differences in the Cardiac Proteome Open
Proteomics studies often explore phenotypic differences between whole organs and systems. Within the heart, more subtle variation exists. To date, differences in the underlying proteome are only described between whole cardiac chambers. Th…
View article: TITINdb2 – Expanding Annotation and Structural Information for Protein Variants in the Giant Sarcomeric Protein Titin
TITINdb2 – Expanding Annotation and Structural Information for Protein Variants in the Giant Sarcomeric Protein Titin Open
Structured Abstract Summary We present TITINdb2, an update to the TITINdb database previously constructed to facilitate the identification of pathogenic missense variants in the giant protein titin, which are associated with a variety of s…
View article: Walking with giants: The challenges of variant impact assessment in the giant sarcomeric protein titin
Walking with giants: The challenges of variant impact assessment in the giant sarcomeric protein titin Open
Titin, the so‐called “third filament” of the sarcomere, represents a difficult challenge for the determination of damaging genetic variants. A single titin molecule extends across half the length of a sarcomere in striated muscle, fulfilli…
View article: Structure of the native myosin filament in the relaxed cardiac sarcomere
Structure of the native myosin filament in the relaxed cardiac sarcomere Open
View article: Unlocking Predictive Power: A Machine Learning Tool Derived from In-Depth Analysis to Forecast the Impact of Missense Variants in Human Filamin C
Unlocking Predictive Power: A Machine Learning Tool Derived from In-Depth Analysis to Forecast the Impact of Missense Variants in Human Filamin C Open
Cardiomyopathies, diseases of the heart muscle, are a leading cause of heart failure. An increasing proportion of cardiomyopathies have been associated with specific genetic changes, such as mutations in FLNC , the gene that codes for fila…
View article: Structure determination and analysis of titin A-band fibronectin type III domains provides insights for disease-linked variants and protein oligomerisation
Structure determination and analysis of titin A-band fibronectin type III domains provides insights for disease-linked variants and protein oligomerisation Open
Titin is the largest protein found in nature and spans half a sarcomere in vertebrate striated muscle. The protein has multiple functions, including in the organisation of the thick filament and acting as a molecular spring during the musc…
View article: Successful heart transplant in a child with congenital core myopathy and delayed‐onset restrictive cardiomyopathy due to recessive mutations in the titin (<i>TTN</i>) gene
Successful heart transplant in a child with congenital core myopathy and delayed‐onset restrictive cardiomyopathy due to recessive mutations in the titin (<i>TTN</i>) gene Open
Background Mutations in the TTN gene, encoding the muscle filament titin, are a major cause of inherited dilated cardiomyopathy. Early‐onset skeletal muscle disorders due to recessive TTN mutations have recently been described, sometimes a…
View article: Obscurin Rho GEF domains are phosphorylated by MST-family kinases but do not exhibit nucleotide exchange factor activity towards Rho GTPases in vitro
Obscurin Rho GEF domains are phosphorylated by MST-family kinases but do not exhibit nucleotide exchange factor activity towards Rho GTPases in vitro Open
Obscurin is a giant muscle protein (>800 kDa) featuring multiple signalling domains, including an SH3-DH-PH domain triplet from the Trio-subfamily of guanosine nucleotide exchange factors (GEFs). While previous research suggests that these…
View article: In situ structures from relaxed cardiac myofibrils reveal the organization of the muscle thick filament
In situ structures from relaxed cardiac myofibrils reveal the organization of the muscle thick filament Open
The thick filament is a key component of sarcomeres, the basic force-generating and load-bearing unit of striated muscle 1 . Mutations in thick filament proteins are associated with familial hypertrophic cardiomyopathy and other heart and …
View article: Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2
Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2 Open
Pathogenic variants in ACTN2, coding for alpha-actinin 2, are known to be rare causes of Hypertrophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 p.Met228Thr …
View article: Obscurin Rho GEF domains are phosphorylated by MST-family kinases but do not exhibit nucleotide exchange factor activity towards Rho GTPases<i>in vitro</i>
Obscurin Rho GEF domains are phosphorylated by MST-family kinases but do not exhibit nucleotide exchange factor activity towards Rho GTPases<i>in vitro</i> Open
Obscurin is a giant muscle protein (>800 kDa) featuring multiple signalling domains, including an SH3-DH-PH domain triplet from the Trio-subfamily of guanosine nucleotide exchange factors (GEFs). While previous research suggests that these…
View article: Structures from intact myofibrils reveal mechanism of thin filament regulation through nebulin
Structures from intact myofibrils reveal mechanism of thin filament regulation through nebulin Open
In skeletal muscle, nebulin stabilizes and regulates the length of thin filaments, but the underlying mechanism remains nebulous. In this work, we used cryo–electron tomography and subtomogram averaging to reveal structures of native nebul…
View article: Structure of the thin filament in native skeletal muscles reveals its interaction with nebulin and two distinct conformations of myosin
Structure of the thin filament in native skeletal muscles reveals its interaction with nebulin and two distinct conformations of myosin Open
Nebulin is a major structural protein of skeletal sarcomeres and is essential for proper assembly and contraction of skeletal muscle 1 . It stabilises and regulates the length of thin filaments, 2 but the structural mechanism remains nebul…
View article: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload
Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload Open
Myopalladin (MYPN) is a striated muscle-specific immunoglobulin domain-containing protein located in the sarcomeric Z-line and I-band. MYPN gene mutations are causative for dilated (DCM), hypertrophic, and restrictive cardiomyopathy. In a …
View article: Sub-diffraction error mapping for localisation microscopy images
Sub-diffraction error mapping for localisation microscopy images Open
View article: Phosphorylation at Serines 157 and 161 Is Necessary for Preserving Cardiac Expression Level and Functions of Sarcomeric Z-Disc Protein Telethonin
Phosphorylation at Serines 157 and 161 Is Necessary for Preserving Cardiac Expression Level and Functions of Sarcomeric Z-Disc Protein Telethonin Open
Aims: In cardiac myocytes, the sarcomeric Z-disc protein telethonin is constitutively bis-phosphorylated at C-terminal residues S157 and S161; however, the functional significance of this phosphorylation is not known. We sought to assess t…
View article: Out-of-Frame Mutations in <i>ACTN2</i> Last Exon Cause a Dominant Distal Myopathy With Facial Weakness
Out-of-Frame Mutations in <i>ACTN2</i> Last Exon Cause a Dominant Distal Myopathy With Facial Weakness Open
Our findings indicate an unusual form of actininopathy with specific molecular and clinical features. Actininopathy should be considered in the differential diagnosis of distal myopathy combined with facial weakness.
View article: The molecular basis for sarcomere organization in vertebrate skeletal muscle
The molecular basis for sarcomere organization in vertebrate skeletal muscle Open
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View article: Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers
Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers Open
View article: Author response: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload
Author response: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload Open
Article Figures and data Abstract Introduction Results Discussion Materials and methods Appendix 1 Data availability References Decision letter Author response Article and author information Metrics Abstract Myopalladin (MYPN) is a striate…
View article: The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy
The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy Open
Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders …
View article: Order from disorder in the sarcomere: FATZ forms a fuzzy but tight complex and phase-separated condensates with α-actinin
Order from disorder in the sarcomere: FATZ forms a fuzzy but tight complex and phase-separated condensates with α-actinin Open
Sarcomeric proteins FATZ-1 and α-actinin-2 associate in a tight fuzzy complex, which forms phase-separated condensates.
View article: Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure
Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure Open
The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCt…
View article: Decision letter: Conformational changes in twitchin kinase in vivo revealed by FRET imaging of freely moving C. elegans
Decision letter: Conformational changes in twitchin kinase in vivo revealed by FRET imaging of freely moving C. elegans Open
Article Figures and data Abstract Introduction Results Discussion Materials and methods Appendix 1 Data availability References Decision letter Author response Article and author information Metrics Abstract The force-induced unfolding and…
View article: The molecular basis for sarcomere organization in vertebrate skeletal muscle
The molecular basis for sarcomere organization in vertebrate skeletal muscle Open
View article: Sub-diffraction error mapping for localization microscopy images
Sub-diffraction error mapping for localization microscopy images Open
Assessing the quality of localization microscopy images is highly challenging due to difficulty in reliably detecting errors in experimental data, with artificial sharpening being a particularly common failure mode of the technique. Here w…