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.
Highlights
Nystagmus presents as involuntary rhythmic eye movements that can have a genetic origin or be acquired during infancy or later in life
Infantile nystagmus may be sub-categorized into idiopathic infantile nystagmus (IIN) without obvious retinal dysfunction or dysmorphology and forms of infantile nystagmus associated with signs of ocular mal-development featuring foveal hypoplasia as in PAX6-linked Aniridia (Azuma et al, 1996) or FHONDA due to mutations in SLC38A8 (Poulter et al, 2013)
We have shown that a homozygous loss of function (LOF) mutation in the aryl hydrocarbon receptor (AHR) gene is associated with autosomal recessively inherited foveal hypoplasia with infantile nystagmus
Summary
Nystagmus presents as involuntary rhythmic eye movements that can have a genetic origin or be acquired during infancy or later in life. Infantile nystagmus may be sub-categorized into idiopathic infantile nystagmus (IIN) without obvious retinal dysfunction or dysmorphology and forms of infantile nystagmus associated with signs of ocular mal-development featuring foveal hypoplasia as in PAX6-linked Aniridia (Azuma et al, 1996) or FHONDA (foveal hypoplasia, optic nerve decussation and outer segment dysgenesis) due to mutations in SLC38A8 (Poulter et al, 2013) These patients typically show mildly reduced visual acuity and an abnormal optokinetic response (OKR) (Thomas et al, 2008; Thomas et al, 2011a; Self et al, 2007). This is further evidenced by abnormalities of OKR and retinal circuitry detected in Frmd knockout mice (Yonehara et al, 2016)
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