Journal Article

Clinical, genetic and biochemical signatures of RBP4-related ocular malformations


Background: The retinoic acid (RA) pathway plays a crucial role in both eye morphogenesis and the visual cycle. Individuals with mono- and bi-allelic pathogenic variants in RBP4, encoding a serum retinol specific transporter, display variable ocular phenotypes. Although few families have been reported worldwide, recessive inherited variants appear to be associated with retinal degeneration, while individuals with dominantly inherited variants manifest ocular development anomalies, mainly microphthalmia, anophthalmia and coloboma (MAC). Method: We report here 7 new families (13 patients) with isolated and syndromic MAC harbouring heterozygous RBP4 variants, to whom we performed biochemical analyses. Results: For the first time, malformations that overlap the clinical spectrum of vitamin A deficiency are reported, providing a link with other RA disorders. Our data support two distinct phenotypes depending on the nature and mode of inheritance of the variants: dominantly inherited, almost exclusively missense, associated with ocular malformations, in contrast to recessive, mainly truncating, associated with retinal degeneration. Moreover, we also confirm the skewed inheritance and impact of maternal RBP4 genotypes on phenotypic expression in dominant forms suggesting that maternal RBP4 genetic status and content of diet during pregnancy may modify MAC occurrence and severity. Furthermore, we demonstrate that RBP blood dosage in patients could provide a biological signature crucial for classifying RBP4 variants. Finally, we propose a novel hypothesis to explain the mechanisms underlying the observed genotype-phenotype correlations in RBP4 mutational spectrum. Conclusion: Dominant missense variants in RBP4 are associated with MAC of incomplete penetrance with maternal inheritance through a likely dominant-negative mechanism. 

Attached files


Plaisancié, Julie
Martinovic, Jelena
Chesneau, Bertrand
Whalen, Sandra
Rodriguez, Diana
Audebert-Bellanger, Séverine
Marzin, Pauline
Grotto, Sarah
Perthus, Isabelle
Holt, Richard
Bax, Dorine
Ragge, Nicola K.
Chassaing, Nicolas

Oxford Brookes departments

Department of Biological and Medical Sciences


Year of publication: 2023
Date of RADAR deposit: 2023-07-21

Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

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