Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus

Abstract

Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C>T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr-/- mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.

Keywords: AHR; consanguinity; foveal hypoplasia; nystagmus.

Figure 1. Pedigree of family TR 16 (NYS 12) and electropherograms of the identified AHR mutation.

Whole-exome sequencing was performed for individual IV:6 and revealed a homozygous nonsense mutation (c.1861C>T;p.Q621*) in the AHR gene. Segregation analysis was performed with all available DNA samples (genotypes underneath; plus sign = wild-type allele). Representative sequences are shown underneath. WT, wild-type; Het, heterozygous; Hom, homozygous.

Figure 2. Optical coherence tomogram through the fovea in individuals IV:5 and IV:6.

Features consistent with grade 3 foveal hypoplasia are seen. These include: lack of a foveal pit (1), incursion of inner retinal layers (2), outer nuclear layer widening (3) and lack of outer segment lengthening (4).