The X‐linked filaminopathies: Synergistic insights from clinical and molecular analysis

Abstract

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...

Postnatal Role of the Cytoskeleton in Adult Epileptogenesis

“…MF-associated proteins regulate the dynamics of actin through polymerization, capping, and severing. In particular, filamin A has the unique ability of holding 2 filaments of actin together, thereby organizing the actin network ( Sutherland-Smith 2011 ; Wade et al. 2020 ).…”

“…2001 ; Paredes and Baraban 2002 ; LoTurco and Bai 2006 ; Wynshaw-Boris 2007 ; Sutherland-Smith 2011 ; Guarnieri et al. 2018 ; Wade et al. 2020 ).…”

FLN-1/Filamin is required to anchor the actomyosin cytoskeleton and for global organization of sub-cellular organelles in a contractile tissue

“…This may explain why the phenotypes we observed are more dramatic than the loss of filamin phenotypes seen in other systems. Various familial filaminopathies are associated with filamin A ,B, and C in humans, although the molecular mechanisms behind these disorders are not well understood (Baudier, Jenkins, & Robertson, 2018;Duff et al, 2011;Ferrer & Olivé, 2008;Kley et al, 2007;Razinia et al, 2012;Vorgerd et al, 2005;Wade, Halliday, Jenkins, O'Neill, & Robertson, 2020). Our work also suggests that in addition to the known roles of filamin as an actin crosslinker and signaling scaffold, loss of filamin in non-redundant systems can result in global rearrangement of the cell cytoskeleton and organelles.…”

FLN‐1/filamin is required to anchor the actomyosin cytoskeleton and for global organization of sub‐cellular organelles in a contractile tissue

“…This may explain why the phenotypes we observed are more dramatic than the loss of filamin phenotypes seen in other systems. Various familial filaminopathies are associated with filamin A, B, and C in humans, although the molecular mechanisms behind these disorders are not well understood (Baudier, Jenkins, & Robertson, 2018;Duff et al, 2011;Ferrer & Olivé, 2008;Kley et al, 2007;Razinia et al, 2012;Vorgerd et al, 2005;Wade, Halliday, Jenkins, O'Neill, & Robertson, 2020). Our work also suggests that in addition to the known roles of filamin as an actin crosslinker and signaling scaffold, loss of filamin in nonredundant systems can result in global rearrangement of the cell cytoskeleton and organelles.…”