Abstract
BackgroundJalili syndrome (JS) is a rare cone‐rod dystrophy (CRD) associated with amelogenesis imperfecta (AI). The first clinical presentation of JS patients was published in 1988 by Jalili and Smith. Pathogenic mutations in the Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4 (CNNM4) magnesium transporter protein have been reported as the leading cause of this anomaly.MethodsIn the present study, a clinical and genetic investigation was performed in a consanguineous family of Pakistani origin, showing characteristic features of JS. Sanger sequencing was successfully used to identify the causative variant in CNNM4. Molecular dynamics (MD) simulations were performed to study the effect of amino acid change over CNNM4 protein.ResultsSequence analysis of CNNM4 revealed a novel missense variant (c.1220G>T, p.Arg407Leu) in exon‐1 encoding cystathionine‐β‐synthase (CBS) domain. To comprehend the mutational consequences in the structure, the mutant p.Arg407Leu was modeled together with a previously reported variant (c.1484C>T, p.Thr495Ile) in the same domain. Additionally, docking analysis deciphered the binding mode of the adenosine triphosphate (ATP) cofactor. Furthermore, 60ns MD simulations were carried out on wild type (p.Arg407/p.Thr495) and mutants (p.Arg407Leu/p.Thr495Ile) to understand the structural and energetic changes in protein structure and its dynamic behavior. An evident conformational shift of ATP in the binding site was observed in simulated mutants disrupting the native ATP‐binding mode.ConclusionThe novel identified variant in CNNM4 is the first report from the Pakistani population. Overall, the study is valuable and may give a novel insight into metal transport in visual function and biomineralization.
Highlights
Cone‐rod dystrophy (CRD; MIM 120970) and amelogenesis imperfecta (AI; MIM 204700), collectively known as Jalili syndrome (JS, MIM 217080), were first reported by Jalili and Smith, (1988)
Cation Transport Mediator 4 (CNNM4) (Q6P4Q7), has a DUF21 domain comprising four transmembrane helices and a leucine‐zipper. Further composition of this protein contains one cyclic nucleotide monophosphate‐binding domain, one cyclin‐box motif domain similar to the one present in ion channels and cNMP‐dependent kinases from residues 548–578, and two CBS domains, which are believed to have a regulatory role in its biological activity (Gómez García et al, 2011)
JS is caused by mutations in CNNM4 (Cyclin M4; MIM 607805), which encodes a protein, involved in the transport of metal ions, most likely magnesium (Mg) (Luder, Gerth‐ Kahlert, Gerth‐Kahlert, Ostertag‐Benzinger, & Schorderet, 2013; Meyer et al, 2010), which is essential for proper function of the photoreceptors in the retina
Summary
Cone‐rod dystrophy (CRD; MIM 120970) and amelogenesis imperfecta (AI; MIM 204700), collectively known as Jalili syndrome (JS, MIM 217080), were first reported by Jalili and Smith, (1988). Several studies have reported the physiological importance of the CBS domain and its essential role in the transport of Mg2+ (Chen, Yang, Yang, Fakih, Kozlov, & Gehring, 2018; Funato & Miki, 2018; Giménez‐Mascarell et al, 2019; Hattori et al, 2009; Ignoul & Eggermont, 2005). The amino acid substitutions in CBS are linked to the loss of activity, which highlights the vital role of adenosine nucleotides (Scott et al, 2004). In CNNM family proteins, CBS domains play a functionally important role in Mg2+ efflux, probably through interactions with adenosine triphosphate (ATP) (Hirata, Funato, Funato, Takano, & Miki, 2014). We further analyzed the structural impact of this novel amino acid substitution (p.Arg407Leu) through MD simulations of an already reported variant (c.1484C>T, p.Thr495Ile) which is stated in CRD patients (Abu‐Safieh et al, 2012)
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