Novel Filamin genes variants implicated in skeletal dysplasias: integrated structural modeling and <i>in silico</i> functional characterization

Skeletal dysplasia is an ensemble of hereditary conditions that impact bone and cartilage formation, leading to aberrant skeletal growth and proportions. Such illnesses can affect the limbs, spine, and skull, and they can produce a wide range of symptoms, from minor to severe. Filamin A and B are functionally analogous proteins, exhibiting structural resemblance and playing crucial role in the formation of cellular cytoskeleton. Objective of the research was to employ experimental and computational approaches to investigate the contribution of Filamins in skeletal dysplasias. Whole exome sequencing lead to the identification of two mutations involved in a spectrum of skeletal dysplasias with predominant spine and articular association. Here we report two families from Pakistan with distinct mutations in FLNA protein (R196W) causing otopalatodigital syndrome-1 or metaepishyseal dysplasia with short stature, prominent facial dysmorphism including hypertelorism, frontal bossing, down-slanting parpebral fissures and depressed nasal bridge. While novel, homozygous, nonsense FLNB mutation (p.C1081*) is causing Spondylocarpotarsal synostosis syndrome (SCT), an exceptionally rare skeletal disorder marked by disproportionate short stature, spinal deformities, and other associated features like dental enamel hypoplasia, joint laxity, and conductive hearing loss. <i>In silico</i> structural and functional analysis of mutant filamins provide compelling proof for their role in the progression of skeletal dysplasias. Screened variants have not only affected the protein's three-dimensional structure dramatically but also resulted in loss of functional domains, leading to aberrant interactions with binding proteins and progression of disease.