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Original research
Clinical, genetic and biochemical signatures of RBP4-related ocular malformations
  1. Julie Plaisancié1,2,3,
  2. Jelena Martinovic4,
  3. Bertrand Chesneau1,3,
  4. Sandra Whalen5,
  5. Diana Rodriguez6,
  6. Séverine Audebert-Bellanger7,
  7. Pauline Marzin8,
  8. Sarah Grotto9,
  9. Isabelle Perthus10,
  10. Richard James Holt11,
  11. Dorine A Bax11,
  12. Nicola Ragge11,12,
  13. Nicolas Chassaing1,3
  1. 1 Laboratoire National de Référence (LBMR), Génétique des anomalies malformatives de l’œil, CHU Toulouse, Toulouse, France
  2. 2 Unité ToNIC Inserm 1214, CHU Toulouse, Toulouse, France
  3. 3 Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), CHU Toulouse, Toulouse, France
  4. 4 Département de Génétique, Unité de Fœtopathologie, Hopital Necker-Enfants Malades, Paris, France
  5. 5 Genetique Medicale, Hopital Armand-Trousseau, Paris, France
  6. 6 Département de Génétique, Hôpitaux Universitaires Paris Ile-de-France Ouest, Paris, France
  7. 7 Service de Génétique Médicale, CHU Brest, Brest, France
  8. 8 Fédération de Génétique et Médecine Génomique, Service de Médecine Génomique des Maladies Rares, Necker-Enfants Malades Hospitals, Paris, France
  9. 9 Maternité Port-Royal, FHU PREMA, Hôpital Cochin, Paris, France
  10. 10 Centre d'Etude des Malformations Congénitales en Auvergne, Génétique Médicale, CHU Estaing, Clermont-Ferrand, France
  11. 11 Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK
  12. 12 West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
  1. Correspondence to Dr Julie Plaisancié, Laboratoire National de Référence (LBMR), Génétique des anomalies malformatives de l’œil, CHU Toulouse, Toulouse, 31059, France; plaisancie.j{at}


Background The retinoic acid (RA) pathway plays a crucial role in both eye morphogenesis and the visual cycle. Individuals with monoallelic and biallelic pathogenic variants in retinol-binding protein 4 (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).

Methods We report here seven new families (13 patients) with isolated and syndromic MAC harbouring heterozygous RBP4 variants, of 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 phenotypical 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 retinol-binding protein 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.

  • Inheritance Patterns
  • Human Genetics
  • Ophthalmology
  • Eye Diseases
  • Genetics, Medical

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • Contributors JP and NC did the study design. JP, BC and NC wrote the manuscript. JM, SW, DR, SAB, PM, SG, IP, DAB and NR did the patients’ evaluation. JP, NC and RJH did the genetic analysis. All the authors reviewed and approved the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.