Gene and Protein Expression in Subjects With a Nystagmus-Associated AHR Mutation

Abstract

Recently, a consanguineous family was identified in Israel with three children affected by Infantile Nystagmus and Foveal Hypoplasia, following an autosomal recessive mode of inheritance. A homozygous stop mutation c.1861C > T; p.Q621 * in the aryl hydrocarbon receptor (AHR) gene (AHR; MIM 600253) was identified that cosegregated with the disease in the larger family. AHR is the first gene to be identified causing an autosomal recessive Infantile Nystagmus-related disease in humans. The goal of this study is to delineate the molecular basis of this newly discovered human genetic disorder associated with a rare AHR gene mutation. The gene and protein expression levels of AHR and selected AHR targets from leukocyte cultures of healthy subjects and the patients were analyzed. We observed significant variation between mRNA and protein expression of CYP1A1, CYP1B1, and TiPARP under rest and AHRinduced conditions. The CYP1A1 enzymatic activity in induced leukocytes also differs significantly between the patients and healthy volunteers. Intriguingly, the heterozygous subjects demonstrate CYP1A1 and TiPARP gene and protein expression similar to homozygous patients. In contrast, CYP1B1 inducibility and expression vary between hetero-and homozygous subjects. Similarity and differences in gene and protein expression between heterozygotes and homozygous patients can give us a hint as to which metabolic pathway/s might be involved in the Nystagmus etiology. Thus, we have a unique human model for AHR deficiency that will allow us the opportunity to study the biochemical basis of this rare human mutation, as well as the involvement of AHR in other physiological processes.

Aryl Hydrocarbon Receptor and Its Diverse Ligands and Functions: An Exposome Receptor

“…The occurrence of a nystagmus has been subsequently diagnosed in humans bearing a AhR mutation (112,113). The demyelination in the CNS is also observed in the peripheral nervous system, potentially due to an altered Wnt/β-catenin signaling (114).…”

More than Meets the Eye: The Aryl Hydrocarbon Receptor is an Environmental Sensor, Physiological Regulator and a Therapeutic Target in Ocular Disease

“…Three children experiencing INS from the same family were found to have a loss of function mutation of the AHR gene. The resulting AHR protein is truncated and missing a portion of the C-terminus ( Mayer et al, 2019 ; Borovok et al, 2020 ). AHR protein expression and function in these patients is decreased to at least half of the level of controls ( Borovok et al, 2020 ).…”

“…The resulting AHR protein is truncated and missing a portion of the C-terminus ( Mayer et al, 2019 ; Borovok et al, 2020 ). AHR protein expression and function in these patients is decreased to at least half of the level of controls ( Borovok et al, 2020 ). As previously mentioned, nystagmus is also observed in AHR knockout mice ( Chevallier et al, 2013 ).…”