The molecular basis of a novel human AhR-mutation disease

A consanguineous family exhibiting idiopathic infantile nystagmus and foveal hypoplasia, following an autosomal recessive mode of inheritance, was shown to have a homozygous c.1861C>T;p.Q621* mutation in the aryl hydrocarbon receptor (AhR) gene (AhR; MIM 600253). The AHR is a ligand-activated transcription factor initially identified as a regulator of xenobiotic metabolism. Activated AHR modulates gene expression and influences biological processes such as apoptosis, proliferation, cell growth and differentiation. AHR has many target genes including drug metabolizing enzymes like those of the CytP450 family.

The main goal of this project is to investigate the biochemical and molecular basis of the AHR disease. We used an enzymatic assay for the CYP1A1 gene product (also known as Aryl Hydrocarbon Hydroxylase, AHH) as a primary target of AhR gene activation, to test inducibility of AHH activity in human lymphocyte cultures. We found that activity is significantly lower in patients, compared with healthy volunteers. These results correlate with relative AHH protein levels, as determined by western blot using AHH antibodies. We then investigated expression of AHR and AHR-related genes using quantitative RT PCR. We found that basal expression of AHR and AHR-inducible genes in lymphocytes culture of patients is lower that of healthy subjects; the inducibility of these genes in the patients is very low as well.

Since the patients did not exhibit any phenotype other than the nystagmus and foveal hypoplasia, we suggest that AHR dysfunction may affect eye development via a pathway that is unrelated to its classic, detoxifying function.