1. Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus
- Author
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Elfride De Baere, Gail Maconachie, Abdussalam Azem, Peter Bauer, Yuval Cohen, Martin Schulze, Birgit Lorenz, Bernd Wissinger, Rajech Sharkia, Basamat Almoallem, Irene Gottlob, Muhammad Mahajnah, Anja K. Mayer, Susanne Kohl, Elias I. Traboulsi, Adib Habib, and Mervyn G Thomas
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,genetic structures ,Consanguinity ,Nystagmus ,Nervous System Malformations ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Basic Helix-Loop-Helix Transcription Factors ,Electroretinography ,medicine ,Animals ,Humans ,Optic Nerve Hypoplasia ,Child ,Exome sequencing ,biology ,business.industry ,Homozygote ,Genetic disorder ,medicine.disease ,Aryl hydrocarbon receptor ,eye diseases ,Hypoplasia ,Pedigree ,030104 developmental biology ,Endocrinology ,Receptors, Aryl Hydrocarbon ,Mutation ,biology.protein ,Albinism ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Nystagmus, Congenital ,030217 neurology & neurosurgery ,Horizontal pendular 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 (WES), 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. The aryl hydrocarbon receptor is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. It was further 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 the mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in the Ahr(-/-) mice appears early in development and presents as conjugate horizontal pendular nystagmus (Chevallier et al., 2013; Juricek et al., 2017). 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.
- Published
- 2019