Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex.

The spike glycoprotein of infectious bronchitis virus (IBV), a coronavirus, is translated as a precursor protein (So), then cleaved into two subunits (S1 and S2) by host cell serine proteases. In this study, we compared the cleavage recognition site of 55 IBV isolates to determine if the cleavage recognition site sequence, which consists of five basic amino acid residues, correlates with host cell range, serotype, geographic origin, and pathogenicity as it does in orthomyxoviruses and paramyxoviruses. The most common cleavage recognition site observed (33 of 55 viruses) was Arg-Arg-Ser-Arg-Arg, representing at least 11 different serotypes. Thus, cleavage recognition site does not appear to correlate with serotype. We also determined that cleavage recognition site sequence does not correlate with pathogenicity because attenuated and pathogenic isolates (different passages of the same virus) contain identical cleavage recognition site sequences. In addition, nephropathogenic strains had the same cleavage recognition site sequence as many nonnephropathogenic isolates. Cleavage recognition site sequence does correlate with viruses in different geographic regions, which may be an important characteristic to examine in epidemiologic studies. An IBV monoclonal antibody neutralization-resistant mutant (NR 18) had an unusual substitution of Ile for Arg at the fourth position, giving the sequence Arg-Arg-Ser-Ile-Arg, which likely prevents cleavage and, thus, destroys the conformationally dependent monoclonal antibody binding epitope. Six residues on the amino-terminal side of the cleavage recognition site are conserved in 31% of the isolates and consist of only one or two basic amino acids. Thus, the number of basic residues around the cleavage recognition site does not appear to correlate with increased cleavability, host cell range, and increased virulence as it does with envelope glycoproteins in orthomyxoviruses and paramyxoviruses.

Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFβ-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.

The X-linked filaminopathies represent a diverse group of clinical conditions, all caused by variants in the gene FLNA. FLNA encodes the widely expressed actin binding protein, filamin A that has multiple roles during embryonic development including cell migration, mechanical sensing, and cell signaling. In this review, we discuss the 10 distinct X-linked filaminopathy conditions that between them affect almost all organ systems, including the brain, skeleton, heart, and skin, highlighting the critical role of this protein in human development. We review each of the phenotypes and discuss their pathogenesis, where known. Assigning pathogenicity to variants in FLNA can prove difficult, especially for missense variants and small indels, in-part because of the X-linked nature of the phenotypes, the overlap of phenotypic features between conditions, and poor understanding of the function of certain protein domains. We outline here approaches to characterize phenotypes, highlight hotspot regions within FLNA commonly mutated in these conditions, and approaches to resolving some variants of uncertain significance. K E Y W O R D S filamin A, filaminopathy, periventricular nodular heterotopia, skeletal dysplasia, X-linked disease 1 | INTRODUCTION Pathogenic variants in FLNA, the X-linked gene that encodes the cytoskeletal protein filamin A (FLNA), cause a diverse spectrum of genetic syndromes with features ranging from impaired brain development to skeletal dysplasias, gastrointestinal disorders, and compromised structure and function of the cardiac valves. To date, eight discrete syndromes are formally associated with variants in FLNA reported in OMIM (MIM# 300017). These are X-linked cardiac valvular dysplasia, congenital short bowel syndrome (also called X-linked congenital idiopathic intestinal pseudo-obstruction), frontometaphyseal dysplasia type I, periventricular nodular heterotopia (PH), Melnick -needles syndrome (MNS), otopalatodigital syndrome type 1 (OPD1), OPD2, and digitocutaneous dysplasia (DCD; formally terminal osseous dysplasia). At least two more entities should be added to this list, isolated thrombocytopenia (Nurden et al., 2011) and a disorder characterized by keloid scarring, joint contractures, and cardiac valvulopathy (Atwal et al., 2016; Lah et al., 2015). Collectively, these conditions have been termed the X-linked filaminopathies.The broad diversity of organ systems affected across this phenotypic spectrum highlight the pivotal role that FLNA plays in human development and its widespread, but not quite ubiquitous, expression (Fox et al., 1998;Robertson et al., 2003Robertson et al., , 2007. Additionally, due to the X chromosomal location of FLNA, the presentation of FLNArelated phenotypes varies between males and females. These factors conspire to make the clinical and molecular diagnosis of FLNA-related disorders challenging.Here, we review the phenotypes associated with mutations in FLNA with emphasis on those that have been newly described since the previous comprehensive review on filaminopat...

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