**2. Pathologies associated with IRBP deficiency**

In pathological conditions in which a deficiency of IRBP exists, an important anomaly of the photoreceptor cells and the visual cycle can be detected which leads in some cases to the development of retinitis pigmentosa, accumulation of the cytotoxic bis-retinoid A2E, cone-rod photoreceptor dystrophy and an elongated myopic eye shape [20–25].

IRBP is linked to an autosomal recessive form of retinitis pigmentosa. A heterozygous T-C transition at the position 3024 [26] and a missense mutation of D1080N [22] have been identified. *In vitro* studies of this mutation have shown that it produces a non-secreted protein that induces endoplasmic reticular (ER) stress [27].

Other studies correlate the presence of *IRBP* gene mutations and the occurrence of high myopia in humans. This myopia was accompanied with retinal dystrophy observed by ocular coherence tomography (OCT) and electroretinography (ERG). The ERG showed a delay and reduction in the amplitude of the waves corresponding to the cone response. The *IRPB* gene mutations were c.3454G > T;p.E1152 and c.1530 T > A;p.Y510 which were predicted to lead to a nonsense mediated decay with a complete loss of IRBP function [21]. These findings correlate with animal studies in which IRBP−/− mice have shown ERG alterations and histological findings affecting cones [25]. This animal model has also shown alterations in eye shape and visual acuity [20].

The relationship between IRBP deficiency and accumulation of the lipofuscin precursor A2E has only be demonstrated experimentally on two different animal models. *IRBP*−/− mice have been shown by HPLC a retinal A2E increase of 2.7-fold [25]. Another study using an animal model with Müller cell dysfunction found a decreased expression of IRBP which was also accompanied with accumulation of A2E [24].
