Journal Article

A Novel Mutation of FOXC1 (P136L) in an Axenfeld–Rieger Syndrome Patient With a Systematized Delusion of Jealousy: A Case Report and Literature Review

Ueno, Shu‐ichi, Iga, Jun‐ichi, Yoshino, Yuta

2024

Overview

Background The main features of Axenfeld–Rieger Syndrome (ARS) are ocular, auditory, neurological, and morphological brain abnormalities. Mutations in forkhead box protein C1 (FOXC1) are among the responsible genes causing ARS, but neuropsychiatric features have rarely been reported. The case of an ARS patient (a 77‐year‐old man) with delusions of jealousy and impairment of working memory, in addition to the main clinical features, glaucoma and leukoencephalopathy, is presented. Methods The mutation in the patient's genome was found with whole exome sequencing and in silico analysis using PolyPhen‐2 and SIFT. Furthermore, AlphaFold2 and PyMOL were used to predict the protein structure based on the mutation. Results A novel mutation at the forkhead domain of FOXC1 gene (c.408C>A, p.Phe136Leu) was found and confirmed in the patient's family, and it was predicted to cause protein damage; the SIFT score was 0, meaning deleterious, and the PolyPhen2 result also indicated damaging (score: 0.997). The predicted protein structure based on the novel mutation was different from that of the native structure. In the literature review, 6 of 95 (6.3%) cases showed neuropsychiatric features. Of them, 5 of 6 (83.3%) mutations were located in the forkhead domain. Conclusion A novel mutation was found in the FOXC1 gene (c.408C>A, p.Phe136Leu), which possibly induces delusions of jealousy and impairment of working memory, as well as features of ARS, by changing the protein structure. Mutations in that domain of the FOXC1 gene may be important not only for ocular abnormalities but also for brain function. The proband (II‐3) and his son (III‐3) have ARS by whole exome sequencing. The audiogram shows bilateral sensorineural hearing loss (red, right ear; blue, left ear). Brain magnetic resonance imaging data from the patient (T2‐weighted‐fluid‐attenuated inversion recovery). Representative dopamine active transporter single photon emission computed tomography and 123I‐MIBG myocardial scintigraphy show normal patterns.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Abnormalities / Age / Aged / Anterior Eye Segment - abnormalities / Anterior Eye Segment - pathology / Atrophy / Axenfeld–Rieger syndrome / Brain / Congenital diseases / Damage / Delusions - genetics / Dementia / Eye Abnormalities - genetics / Eye Abnormalities - pathology / Eye Diseases, Hereditary - genetics / Eye Diseases, Hereditary - pathology / Family medical history / Forkhead protein / Forkhead Transcription Factors - chemistry / Forkhead Transcription Factors - genetics / FOXC1 / FOXC1 gene / Functional anatomy / Gene sequencing / Genes / Genetic counseling / Genomes / Genomic analysis / Glaucoma / Hearing loss / Humans / Impairment / Jealousy / Leukoencephalopathy / literature review / Literature reviews / Male / Memory / Morphology / Mutation / Mutation, Missense / neuropsychiatric symptoms / Original / Otolaryngology / Patients / Pedigree / Protein structure / Proteins / Structure-function relationships / Whole genome sequencing