Editorial of Special Issue “Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches”

The Special Issue on “Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches” has published interesting and useful review articles and original experimental articles on fibrodysplasia ossificans progressiva (FOP), a very rare genetic disorder for which much effort is being devoted to search for a cure. In this editorial, I briefly cite the essential content of all the published articles.

Frameshift Variant in ARID2 in a Chilean Individual with Coffin–Siris Syndrome Phenotype

Coffin–Siris syndrome (CSS) is one of the several causes of intellectual disability (ID) and, since its first description, has posed diagnostic challenges given its variability and phenotypic overlap with other alterations of chromatin-remodeling-associated syndromes. It is genetically heterogeneous, and causative mutations are detected in less than 70% of cases. The different subtypes of the syndrome described to date are caused by mutations in genes that encode subunits of the SWI/SNF chromatin-remodeling complex, which plays an essential role in the regulation of gene expression during embryogenesis. Whole exome sequencing (WES) has allowed the identification of pathogenic mutations in these genes, including ARID2. ARID2 is one of the primary components of the SWI/SNF complex and has been associated with ID and phenotypes similar to CSS for the first time in 2015. Fifteen published case reports have identified loss-of-function mutations, suggesting that the underlying pathogenic disease mechanism is haploinsufficiency of ARID2.We herein presented the case of an 8-year-old Chilean girl with clinical suspicion of CSS, in whom a novel frameshift variant in ARID2 was identified by WES. She was the first reported case in Latin America to our knowledge and her phenotype displays the main clinical features suggestive of CSS described in other patients with ARID2 variants. However, she did not present behavioral abnormalities, a characteristic frequently reported in the majority of patients with ARID2 variants, and also had some features, such as sparse scalp hair, which is frequently reported as a manifestation of CSS, but is uncommon in this new group of patients.

A novel disease mechanism leading to the expression of a disallowed gene in the pancreatic beta-cell identified by non-coding, regulatory mutations controlling HK1

Gene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function. This silencing is largely controlled by non-coding elements and their disruption might cause human disease. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo mutations affecting a 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 (HK1), a pancreatic beta-cell disallowed gene. We demonstrated that these mutations resulted in expression of HK1 in the pancreatic beta-cells causing inappropriate insulin secretion and congenital hyperinsulinism. These mutations identify a regulatory region critical for cell-specific silencing. Importantly, this has revealed a new disease mechanism for non-coding mutations that cause inappropriate expression of a disallowed gene.

Immunoglobulin G1 Fc glycosylation as an early hallmark of severe COVID-19

Background Immunoglobulin G1 (IgG1) effector functions are impacted by the structure of fragment crystallizable (Fc) tail-linked N-glycans. Low fucosylation levels on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein specific (anti-S) IgG1 has been described as a hallmark of severe coronavirus disease 2019 (COVID-19) and may lead to activation of macrophages via immune complexes thereby promoting inflammatory responses, altogether suggesting involvement of IgG1 Fc glycosylation modulated immune mechanisms in COVID-19. Methods In this prospective, observational single center cohort study, IgG1 Fc glycosylation was analyzed by liquid chromatography - mass spectrometry following affinity capturing from serial plasma samples of 159 SARS-CoV-2 infected patients. Findings At baseline close to disease onset, anti-S IgG1 glycosylation was highly skewed when compared to total plasma IgG1. A rapid, general reduction in glycosylation skewing was observed during the disease course. Low anti-S IgG1 galactosylation and sialylation as well as high bisection were early hallmarks of disease severity, whilst high galactosylation and sialylation and low bisection were found in patients with low disease severity. In line with these observations, anti-S IgG1 glycosylation correlated with various inflammatory markers. Interpretation Association of low galactosylation, sialylation as well as high bisection with disease severity suggests that Fc-glycan modulated interactions contribute to disease mechanism. Further studies are needed to understand how anti-S IgG1 glycosylation may contributes to disease mechanism and to evaluate its biomarker potential. Funding This project received funding from the European Commission's Horizon2020 research and innovation program for H2020-MSCA-ITN IMforFUTURE, under grant agreement number 721815.

Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy

Several mutations identified in phospholamban (PLN) have been linked to familial dilated cardiomyopathy (DCM) and heart failure, yet the underlying molecular mechanism remains controversial. PLN interacts with sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and regulates calcium uptake, which is modulated by the protein kinase A (PKA)-dependent phosphorylation of PLN during the fight-or-flight response. Here, we present the crystal structures of the catalytic domain of PKA in complex with wild-type and DCM-mutant PLNs. Our structures, combined with the results from other biophysical and biochemical assays, reveal a common disease mechanism: the mutations in PLN reduce its phosphorylation level by changing its conformation and weakening its interactions with PKA. In addition, we demonstrate that another more ubiquitous SERCA-regulatory peptide, called another-regulin (ALN), shares a similar mechanism mediated by PKA in regulating SERCA activity.

Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy

Several variants of the enzyme pyridox(am)ine 5′-phosphate oxidase (PNPO), responsible for a rare form of vitamin B6-dependent neonatal epileptic encephalopathy known as PNPO deficiency (PNPOD), have been reported. However, only a few of them have been characterised with respect to their structural and functional properties, despite the fact that the knowledge of how variants affect the enzyme may clarify the disease mechanism and improve treatment. Here, we report the characterisation of the catalytic, allosteric and structural properties of recombinantly expressed D33V, R161C, P213S, and E50K variants, among which D33V (present in approximately 10% of affected patients) is one of the more common variants responsible for PNPOD. The D33V and E50K variants have only mildly altered catalytic properties. In particular, the E50K variant, given that it has been found on the same chromosome with other known pathogenic variants, may be considered non-pathogenic. The P213S variant has lower thermal stability and reduced capability to bind the FMN cofactor. The variant involving Arg161 (R161C) largely decreases the affinity for the pyridoxine 5′-phosphate substrate and completely abolishes the allosteric feedback inhibition exerted by the pyridoxal 5′-phosphate product.

Intragenic Deletion of the ZMYND11 Gene in 10p15.3 is Associated with Developmental Delay Phenotype: A Case Report

Submicroscopic 10p15.3 microdeletions were previously reported to be associated with developmental delay, and the smallest region of overlap of 10p15.3 deletion including <i>DIP2C</i> and <i>ZMYND11</i> was defined. Moreover, pathogenic <i>ZMYND11</i> truncating variants were subsequently identified in a cohort of patients with developmental delay. Of interest, patients harboring 10p15.3 microdeletions or pathogenic <i>ZMYND11</i> truncating variants share similar clinical features including hypotonia, intellectual disability, facial dysmorphisms, speech and motor delays, seizures, and significant behavioral problems. Only 1 patient with whole <i>ZMYND11</i> gene deletion was recorded, and no intragenic <i>ZMYND11</i> deletion was reported up to date. Here, we describe a 7-year-old boy with developmental delay, carrying the smallest de novo 10p15.3 microdeletion, harboring the 5′UTR and the first 2 exons of <i>ZMYND11.</i> Taken together, our report contributes to expand the clinical and mutational spectrum of <i>ZMYND11</i> and confirms haploinsufficiency as the underlying disease mechanism.