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Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast ( TNNI2 ) and TnI-slow ( TNNI1 ), are predominantly expressed in fast- and slow-twitch myofibers, respectively. TNNI2 variants are a rare cause of arthrogryposis, whereas TNNI1 variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function TNNI1 variants as well as dominant gain-of-function TNNI1 variants as a cause of muscle disease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelic TNNI1 variants (F1: p.R14H/c.190-9G>A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifesting with early-onset progressive muscle weakness and rod formation on histology. We also identified two families with a dominantly acting heterozygous TNNI1 variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifesting with muscle cramping, myalgias, and rod formation in F5. In zebrafish, TnI proteins with either of the missense variants (p.R14H; p.R174Q) incorporated into thin filaments. Molecular dynamics simulations suggested that the loss-of-function p.R14H variant decouples TnI from TnC, which was supported by functional studies showing a reduced force response of sarcomeres to submaximal [Ca 2+ ] in patient myofibers. This contractile deficit could be reversed by a slow skeletal muscle troponin activator. In contrast, patient myofibers with the gain-of-function p.R174Q variant showed an increased force to submaximal [Ca 2+ ], which was reversed by the small-molecule drug mavacamten. Our findings demonstrated that TNNI1 variants can cause muscle disease with variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype, suggesting rational therapeutic strategies for each mechanism.

Background: Until now, no laboratory test or test set can guarantee the diagnosis of multiple sclerosis (MS) at early disease stages, and the disease symptoms may interfere with many other disease conditions. Analyzing the expression of circulating miRNAs may provide a useful approach for early and differential MS diagnosis. The main objective is assessment of the potential of serum miR-23a, miR-155, and miR-572 to differentiate between MS and other neuroinflammatory diseases., Methods: Serum miRNAs were obtained from 37 MS patients and 25 healthy age-matched controls, along with patients with neuromyelitis optica spectrum disorder (NMOSD) [n = 13] and neuropsychiatric systemic lupus erythematosus (NPSLE) [n = 10]. miRNA expression levels were analyzed using real-time polymerase chain reaction (PCR) and pairwise comparisons were made to reveal the diagnostic/distinguishing potential of the analyzed miRNAs., Results: In the study cohort, the three investigated miRNAs failed to display significant dysregulation in MS patients. However, they could significantly discriminate patients with NMOSD and NPSLE [median (IQR): 8.1 (6.1-9.2) and 8.8 (7.9-9.7) for miR-23a, 7.5 (5.3-8.3) and 8.0 (7.5-9.5) for miR-155 and 6.9 (5.0-8.8) and 6.4 (5.3-8.8) for miR-572 in NMOSD and NPSLE, respectively] from healthy subjects [median (IQR): 3.4 (1.5-4.3), 3.1 (1.1-5.6) and 3.5 (1.7-5.6) for miR-23a, miR-155 and miR-572, respectively], with area under the curve (AUC) ≤0.8. Remarkably, miR-23a has been emerging as a prospective biomarker for differentiation of MS from NMOSD as well as NPSLE (AUC<0.9). The miRNA combined use contributed to enhanced diagnostic and discriminatory performance in the study groups., Conclusion: Certain miRNA expression levels would contribute to discriminating MS from other neuroinflammatory diseases., (© 2020 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Objectives Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is a common autosomal recessive disorder caused by defects in the CYP21A2 gene. We aimed to determine the prevalence of the most commonly reported mutations among 21-OHD Egyptian patients and correlate genotype with phenotype. Methods Molecular analysis of the CYP21A2 gene was performed for the detection of the six most common point mutations (p.P30L, p.I172N, p.V281L, p.Q318X, the splice site mutation Int2 [IVS2-13A/C>G], and the cluster of three mutations [p.I236N, p.V237E, and p.M239K] designed as CL6). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed on 47 unrelated Egyptian 21α-OH deficiency patients and their available parents to detect the presence of the six most common point mutations. Results Screening for the six most common point mutations in CYP21A2 gene, revealed mutations in 87.2% (82/94) of the studied alleles corresponding to 47 Egyptian patients. The most common mutation among the studied cases was IVS2-13C/A>G that was found to be presented in a frequency of 46.8% (44/94). The genotype/phenotype correlations related to null, A, and B groups were with PPV of 100, 55.5, and 83.3%, respectively. Conclusions The described method diagnosed CAH in 80.8% of the studied patients. Good correlation between genotype and phenotype in salt wasting and simple virilizing forms is determined, whereas little concordance is seen in nonclassical one. Furthermore, studying the carrier frequency of 21-OHD among the normal population is of great importance.