top of page
Mar 29, 2016

Retinitis pigmentosa associated with a mutation in BEST1

Lauren A Dalvin, Jackson E Abou Chehade, John Chiang, Josefine Fuchs, Raymond Iezzi, Alan D Marmorstein | American Journal Ophthalmology Case Reports | 2016 Mar 30 | Vol 2 | pages 11–17 | doi:10.1016/j.ajoc.2016.03.005


Purpose

There is only one prior report associating mutations in BEST1 with a diagnosis of retinitis pigmentosa (RP). The imaging studies presented in that report were more atypical of RP and shared features of autosomal recessive bestrophinopathy and autosomal dominant vitreoretinochoroidopathy. Here, we present a patient with a clinical phenotype consistent with classic features of RP.


Observations

The patient in this report was diagnosed with simplex RP based on clinically-evident bone spicules with characteristic ERG and EOG findings. The patient had associated massive cystoid macular edema which resolved following a short course of oral acetazolamide. Genetic testing revealed that the patient carries a novel heterozygous deletion mutation in BEST1 which is not carried by either parent. While this suggests BEST1 is causative, the patient also inherited heterozygous copies of several mutations in other genes known to cause recessive retinal degenerative disease.


Conclusions and Importance

How some mutations in BEST1 associate with peripheral retinal degeneration phenotypes, while others manifest as macular degeneration phenotypes is currently unknown. We speculate that RP due to BEST1 mutation requires mutations in other modifier genes.


1. Introduction

Mutations in the gene BEST1 (MIM 607854), which encodes the protein Bestrophin-1 (Best1), are responsible for 5 clinically distinct inherited retinopathies: Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and retinitis pigmentosa (RP) [1], [2], [3], [4], [5], [6], [7]. While mutations in BEST1 are widely accepted to cause BVMD, AVMD, ARB, and ADVIRC, there has been only one prior report of mutations in BEST1 causing RP [7]. The clinical images in that paper shared phenotypic features of ARB and ADVIRC, causing some to question whether the subjects in the study have classic RP, and thus, whether BEST1 can cause RP [8].


BEST1 encodes bestrophin 1 (Best1) a homo-oligomeric anion channel that, within the eye, is exclusively expressed in retinal pigment epithelial (RPE) cells, where it normally localizes to the basolateral plasma membrane and plays a critical role in regulating Ca2+ signaling [9], [10], [11]. BEST1 mutations are typically thought to be disease-causing when they result in loss of anion-channel activity [12], [13]. Previous studies have shown that the first ∼174 amino acids of Best1 are sufficient to permit oligomerization and that the first ∼366 amino acids are sufficient for both homo-oligomerization and channel activity [14], [15]. It has also been demonstrated that mislocalization alone is not pathogenic [14].


Here, we present a patient with RP due to a deletion mutation in BEST1, H422fsX431.



 

References

  1. Marquardt A., Stohr H., Passmore L.A., Kramer F., Rivera A., Weber B.H. Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease) Hum. Mol. Genet. 1998;7:1517–1525. doi: 10.1093/hmg/7.9.1517. [DOI] [PubMed] [Google Scholar]

  2. Marmorstein A.D., Cross H.E., Peachey N.S. Functional roles of bestrophins in ocular epithelia. Prog. Retin Eye Res. 2009;28:206–226. doi: 10.1016/j.preteyeres.2009.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

  3. Petrukhin K., Koisti M.J., Bakall B. Identification of the gene responsible for best macular dystrophy. Nat. Genet. 1998;19:241–247. doi: 10.1038/915. [DOI] [PubMed] [Google Scholar]

  4. Kramer F., White K., Pauleikhoff D. Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration. Eur. J. Hum. Genet. 2000;8:286–292. doi: 10.1038/sj.ejhg.5200447. [DOI] [PubMed] [Google Scholar]

  5. Burgess R., Millar I.D., Leroy B.P. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am. J. Hum. Genet. 2008;82:19–31. doi: 10.1016/j.ajhg.2007.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

  6. Yardley J., Leroy B.P., Hart-Holden N. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC) Investig. Ophthalmol. Vis. Sci. 2004;45:3683–3689. doi: 10.1167/iovs.04-0550. [DOI] [PubMed] [Google Scholar]

  7. Davidson A.E., Millar I.D., Urquhart J.E. Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. Am. J. Hum. Genet. 2009;85:581–592. doi: 10.1016/j.ajhg.2009.09.015. [DOI] [PMC free article] [PubMed] [Google Scholar]

  8. Leroy B.P. Bestrophinopathies. In: Traboulsi E.I., editor. Genetic Diseases of the Eye. second ed. Oxford Univ. Press; New York: 2012. p. 434. [Google Scholar]

  9. Marmorstein A.D., Marmorstein L.Y., Rayborn M., Wang X., Hollyfield J.G., Petrukhin K. Bestrophin, the product of the best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc. Natl. Acad. Sci. U. S. A. 2000;97:12758–12763. doi: 10.1073/pnas.220402097. [DOI] [PMC free article] [PubMed] [Google Scholar]

  10. Marmorstein L.Y., Wu J., McLaughlin P. The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1) J. Gen. Physiol. 2006;127:577–589. doi: 10.1085/jgp.200509473. [DOI] [PMC free article] [PubMed] [Google Scholar]

  11. Zhang Y., Stanton J.B., Wu J. Suppression of Ca2+ signaling in a mouse model of best disease. Hum. Mol. Genet. 2010;19:1108–1118. doi: 10.1093/hmg/ddp583. [DOI] [PMC free article] [PubMed] [Google Scholar]

  12. Hartzell H.C., Qu Z., Yu K., Xiao Q., Chien L.T. Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. Physiol. Rev. 2008;88:639–672. doi: 10.1152/physrev.00022.2007. [DOI] [PubMed] [Google Scholar]

  13. Xiao Q., Hartzell H.C., Yu K. Bestrophins and retinopathies. Pflugers Arch. 2010;460:559–569. doi: 10.1007/s00424-010-0821-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

  14. Johnson A.A., Lee Y.S., Chadburn A.J. Disease-causing mutations associated with four bestrophinopathies exhibit disparate effects on the localization, but not the oligomerization, of Bestrophin-1. Exp. Eye Res. 2014;121:74–85. doi: 10.1016/j.exer.2014.02.006. [DOI] [PMC free article] [PubMed] [Google Scholar]







Comments

bottom of page