LMOD2-related dilated cardiomyopathy presenting in late infancy.

Dilated cardiomyopathy is a rare but severe myocardial disease in the paediatric population, often leading to heart failure, heart transplantation, or sudden cardiac death. Genetic factors are a major contributor to childhood dilated cardiomyopathy. Recently, biallelic variants in the PPP1R13L gene have been implicated in a novel syndromic form of early-onset dilated cardiomyopathy, characterised by cardiac dysfunction alongside variable ectodermal features. We report a 4-year-old boy who presented with decompensated heart failure and echocardiographic findings consistent with dilated cardiomyopathy. Syndromic features included sparse, dry hair, high anterior hairline, broad nasal bridge, and pointed teeth. Genetic analysis revealed a novel homozygous frameshift variant in the PPP1R13L gene (c.2368_2375dup; p. Pro793Glyfs*32), classified as pathogenic. The clinical course was complicated by recurrent ventricular arrhythmias and ultimately sudden cardiac death. PPP1R13L-related cardiomyopathy should be considered in children with early-onset dilated cardiomyopathy and syndromic features. Early diagnosis is critical for clinical management, arrhythmia surveillance, and appropriate family counselling.

The actin containing tropomyosin and troponin decorated thin filaments form one of the crucial components of the contractile apparatus in muscles. The thin filaments are organized into densely packed lattices interdigitated with myosin-based thick filaments. The crossbridge interactions between these myofilaments drive muscle contraction, and the degree of myofilament overlap is a key factor of contractile force determination. As such, the optimal length of the thin filaments is critical for efficient activity, therefore, this parameter is precisely controlled according to the workload of a given muscle. Thin filament length is thought to be regulated by two major, but only partially understood mechanisms: it is set by (i) factors that mediate the assembly of filaments from monomers and catalyze their elongation, and (ii) by factors that specify their length and uniformity. Mutations affecting these factors can alter the length of thin filaments, and in human cases, many of them are linked to debilitating diseases such as nemaline myopathy and dilated cardiomyopathy.

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.

The lengths of the sarcomeric thin filaments vary in a skeletal muscle-specific manner and help specify the physiological properties of skeletal muscle. Since the extent of overlap between the thin and thick filaments determines the amount of contractile force that a sarcomere can actively produce, thin filament lengths are accurate predictors of muscle-specific sarcomere length-tension relationships and sarcomere operating length ranges. However, the striking uniformity of thin filament lengths within sarcomeres, specified during myofibril assembly, has led to the widely held assumption that thin filament lengths remain constant throughout an organism's lifespan. Here, we rigorously tested this assumption by using computational super-resolution image analysis of confocal fluorescence images to explore the effects of postnatal development and aging on thin filament length in mice. We found that thin filaments shorten in postnatal tibialis anterior (TA) and gastrocnemius muscles between postnatal days 7 and 21, consistent with the developmental program of myosin heavy chain (MHC) gene expression in this interval. By contrast, thin filament lengths in TA and extensor digitorum longus (EDL) muscles remained constant between 2 mo and 2 yr of age, while thin filament lengths in soleus muscle became shorter, suggestive of a slow-muscle-specific mechanism of thin filament destabilization associated with aging. Collectively, these data are the first to show that thin filament lengths change as part of normal skeletal muscle development and aging, motivating future investigations into the cellular and molecular mechanisms underlying thin filament adaptation across the lifespan.

Novel homozygous variants in piRNA pathway factors lead to male infertility in humans.

Thin filament length in the cardiac sarcomere varies with sarcomere length but is independent of titin and nebulin

Alström syndrome (AS, OMIM #203800) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in ALMS1, characterized by obesity, cardiomyopathy, retinal dystrophy, sensorineural hearing loss, and progressive hepatic and renal involvement. We report a pediatric case of AS complicated by growth hormone deficiency (GHD), focusing on the clinical course and potential metabolic effects of growth hormone (GH) replacement therapy. A 13-year-old girl with AS presented with severe dyslipidemia, including hypertriglyceridemia (727 mg/dL), elevated total cholesterol (251 mg/dL), and low high-density lipoprotein cholesterol (23 mg/dL), together with dilated cardiomyopathy. She was diagnosed with GHD at 3years of age, with a height of-3.6 SD. GH replacement therapy led to sustained improvement in linear growth, reaching-1.9 SD, and was associated with long-term maintenance of lipid parameters within the normal range. Whole-exome sequencing identified a previously unreported homozygous frameshift variant in ALMS1 (NM_001378454.1:c.5763del; p.(Phe1921Leufs*18)). This case suggests that GH replacement therapy may contribute to improved lipid metabolism in patients with AS complicated by GHD. In addition, it expands the mutational spectrum of ALMS1 and highlights the potential metabolic benefits of early endocrine intervention inAS.

The 100 000 Genomes Project (100KGP) is a UK-wide initiative that has a goal of using whole genome sequencing (WGS) to identify genetic causes of rare inherited diseases and embed...

<b>Background:</b> Heart failure is a leading cause of death in industrialized nations especially in the aging populations. Novel approaches to treat the heart after acute injury and to improve cardiac hypertrophic remodeling and heart failure processes remain unsatisfactory. Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP­response element­binding protein family of transcriptional factors. It can be induced by stress condition in a variety of tissues, including cardiac hypertrophy. However, the role of ATF3 or miRs- regulated ATF3 as therapeutic approaches for cardiac hypertrophic remodeling and heart failure is still unclear. <b>Methods and Results:</b> Our recent study revealed that ATF3 can protect against pressure overload-induced heart failure. We demonstrated that ATF3 KO mice has rapid progression to cardiac dilation without proper hypertrophic remodeling after trans-aortic banding (TAB), we then infused tert-butylhydroquinone, a selective ATF3 inducer, which inhibited TAB induced cardiac dilatation and increased left ventricular contractility thus rescue heart failure. We used IPA database analysis to identify the miRs- regulated ATF3 as therapeutic approaches for cardiac hypertrophic remodeling. One specific miRNA, miR-494, initially found in human retinoblastoma tissue, was identified and confirmed to have direct interaction with ATF3 in our H9C2 cells. We then generated miR-494 transgenic mice and demonstrated that miR-494 can be specifically expressed in the heart tissue in our miR-494 transgenic mice. We found that ATF3 expression were markedly decrease in miR-494 transgenic mice receiving TAB treatment as compared to wild type (WT) mice, at 8 weeks and 12 weeks periods after TAB treatment. In addition, echocardiography data showed impaired LV contractility with worsen left ventricular chamber dilatation and wall thinning in miR-494 transgenic mice as compared to WT TAB mice, 12 weeks after TAB treatment. Cardiac hypertrophic markers, including atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and β-MHC, were decreased in miR-494 transgenic mice 8 week after TAB, but not in the WT mice. In addition, down regulation of SIRT1 was observed in miR-494 mice after 8 week, post TAB treatment compared to WT. <b>Conclusions:</b> These results suggest that miR-494 repressed ATF3 expression in cardiac hypertrophic remodeling via suppressing beneficial hypertrophic markers in vivo. Therefore, suppression of this specific miR-494-ATF3 signaling pathway thus to activate ATF3 expression may ameliorate heart failure in cardiac hypertrophic remodeling and can be a potential therapeutic target.

Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle, systolic dysfunction, and normal or reduced thickness of the left ventricular wall. It is a leading cause of heart failure and cardiac death at a young age. Cases with neonatal onset DCM were correlated with severe clinical presentation and poor prognosis. A monogenic molecular etiology accounts for nearly half of cases. Here, we report a family with three deceased offspring at the age of 1 year old. The autopsy of the first deceased infant revealed a DCM. The second infant presented a DCM phenotype with a severely reduced Left Ventricular Ejection Fraction (LVEF) of 10%. Similarly, the third infant showed a severe DCM phenotype with LVEF of 30% as well, in addition to eccentric mitral insufficiency. Exome sequencing was performed for the trio (the second deceased infant and her parents). Data analysis following the autosomal dominant and recessive patterns of inheritance was carried out along with a mitochondrial pathways-based analysis. We identified a homozygous frameshift variant in the TNNI3 gene (c.204delG; p.(Arg69AlafsTer8)). This variant has been recently reported in the ClinVar database in association with cardiac phenotypes as pathogenic or likely pathogenic and classified as pathogenic according to ACMG. Genetic counseling was provided for the family and a prenatal diagnosis of choronic villus was proposed in the absence of pre-implantation genetic diagnosis possibilities. Our study expands the case series of early-onset DCM patients with a protein-truncating variant in the TNNI3 gene by reporting three affected infant siblings.

Bi-allelic variants in NRDC cause a neurodevelopmental disorder characterized by neonatal lethality, microcephaly, and brain abnormalities.

Thin filament length regulation in striated muscle sarcomeres: Pointed-end dynamics go beyond a nebulin ruler

The carpopodite flexor of the walking legs of the crab Portunus depurator contains fibres belonging to 3 groups. These are characterized by differences in the cross-striation spacing. Fibres having sarcomeres of approximately 4, 5 and 7 μm are here called short, medium and long sarcomere types, respectively. Within individual fibres belonging to any of the groups the length of the A band is not constant. Up to 25 % length differences have been measured in A bands belonging even to the same fibril. The bridge-free regions of the thick filaments are not always in the centre, so that the filaments are often asymmetric. Analogally, the L line, resulting from the alignment of the bridge-free regions of the thick filaments, may be asymmetrically placed in the Z band. The length of the bridge-free region in crab thick filaments is 60 nm, while the corresponding region in vertebrate thick filaments is 120 nm. This is discussed in terms of a possible model of the filament. The length of the thin filaments is proportional to that of the thick filaments in the corresponding portion of the sarcomere. When two A bands of different length occur in adjacent positions along the fibril, the Z line is not a centre of symmetry. The ratio of thin to thick filament number is variable in individual fibrils. In general, the ratio is higher in the medium sarcomere type fibres than in the short sarcomere type. Stretched and shorter portions of single fibres of the medium type have been examined and the A-band length populations compared. From such a study it can be deduced that passive length changes occur in crab fibres by sliding of thin and thick filaments.

Thin Filament Pointed Ends Redistribute in Response to Altered Thick Filaments

Sitosterolemia in Iberoamerican countries: 16 new cases and phenotype genotype analysis.