Exploring the Role of FICD, a New Potential Gene Involved in Borderline Intellectual Functioning, Psychological and Metabolic Disorders

Abstract

Background/Objectives: AMPylation is a post-translational modification involving the transfer of adenosine monophosphate (AMP) from adenosine triphosphate (ATP) to target proteins, serving as a critical regulatory mechanism in cellular functions. This study aimed to expand the phenotypic spectrum associated with mutations in the FICD gene, which encodes an adenyltransferase enzyme involved in both AMPylation and deAMPylation. Methods: A clinical evaluation was conducted on a patient presenting with a complex clinical profile. Whole-exome sequencing (WES) was performed to identify potential genetic variants contributing to the observed phenotype. Results: The patient exhibited borderline intellectual functioning (BIF), acanthosis, abdominal muscle hypotonia, anxiety, depression, obesity, and optic nerve subatrophy. WES revealed a de novo missense variant, c.1295C>T p.Ala432Val, in the FICD gene. This variant, classified as of uncertain significance, is located in the highly conserved region TLLFATTEY (aa 428-436), suggesting a potential impact on protein function. Conclusions: These findings highlight the importance of the FICD gene in diverse clinical manifestations and emphasize the need for further studies to elucidate the genetic mechanisms underlying these phenotypes. Continued research is essential to improve our understanding of FICD-related conditions.

Keywords: AMPylation; adenyltransferase; deAMPylation; next-generation sequencing.

Figure 1

Graphical representation of Next-Generation Sequencing (NGS) analysis for identifying the c.1295C>T variant within the FICD gene (NM_007076). (a) Chromosomal localization of the FICD gene, with a specific focus on the DNA and amino acid sequences surrounding the c.1295C>T (p.Ala432Val) variant. (b) Whole-exome sequencing (WES) analysis of the patient, mother, and father, revealing the heterozygous de novo c.1295C>T variant in the patient. This variant is clearly visible using the Integrative Genome Viewer (IGV) tool. (c) Confirmation of the variant through conventional Sanger sequencing for the patient, mother, and father.

Figure 2

Graphical representation of the wild-type and mutated FICD protein structure predictions. (a) Predicted structure of the wild-type FICD protein. (b) Close-up view of the wild-type Ala432 residue forming a hydrogen bond with Thr428. (c) Predicted structure of the mutated FICD protein. (d) Close-up of the mutated Val432 residue establishing a hydrogen bond interaction with Thr428. (a–d) were generated using the UCSF ChimeraX protein modeling software. (e) Graphical representation of the functional domains within the FICD protein, with domain colors consistent with those used in (a,c). The mutation site within the conserved “TLLFATTEY” (aa 428–436) motif is highlighted by a red arrow. (e) was modified from the UniProt database. As annotated by the Uniprot database, FICD has several active and binding sites, precisely located at positions 234, 316–319, 363, 367–374, 399–400, and 407.

Figure 3

Protein–Protein Interaction and Hydrogen Bond Variations in FICD Homodimerization. (a) Graphical representation of the wild-type FICD homodimer, with one FICD protein shown in blue. (b) Close-up of hydrogen bonds within the wild-type FICD homodimer. Blue labels mark residues from one FICD molecule, while red labels indicate interacting residues from the second molecule. (c) Graphical representation of the FICD homodimer involving the p.Ala432Val mutant (blue) and the corresponding partner FICD (red). A black circle and arrow highlight the additional hydrogen bond between Trp17 of the mutant and Val12 of the partner protein. (d) Detailed view of the Trp17-Val12 interaction unique to the mutated FICD homodimer.

Figure 4

Graphical representation of the predicted interaction between FICD and HSPA5 (BiP). (a) Representation of the protein–protein interaction involving the wild-type FICD (blue color) and HSPA5 (red color) proteins. (b) Prediction of the interaction between the FICD protein (blue color) carrying the mutation p.Ala432Val and HSPA5 (red color).