Skip to main content
NCBI home page
The British Journal of Ophthalmology logoLink to The British Journal of Ophthalmology
. 2001 Sep;85(9):1098–1103. doi: 10.1136/bjo.85.9.1098

Deletion in the OA1 gene in a family with congenital X linked nystagmus

M Preising 1, J-P O de Laak 1, B Lorenz 1
PMCID: PMC1724103  PMID: 11520764

Abstract

AIMS—To elucidate the molecular genetic defect of X linked congenital nystagmus associated with macular hypoplasia in three white males of a three generation family with clear features of ocular albinism in only one of them.
METHODS—A three generation family with congenital nystagmus following X linked inheritance, and associated with macular hypoplasia was clinically examined (three males and two obligate carriers). Flash VEP was performed to look for albino misrouting. DNA samples were subjected to PCR and subsequent analysis using SSCP for all exons of the OA1 gene. RT-PCR was performed on a mRNA preparation from a naevus from one patient. PCR products presenting divergent banding patterns in SSCP and from the RT-PCR were sequenced directly using cycle sequencing with fluorescent chain termination nucleotides and electrophoresis in a capillary sequencer.
RESULTS—The index case (patient 1, IV.1) was diagnosed with X linked OA1 at the age of 3 months because of typical clinical features: congenital nystagmus, iris translucency, macular hypoplasia, fundus hypopigmentation, normal pigmentation of skin and hair, and typical carrier signs of OA1 in his mother and maternal grandmother. Pigmentation of the iris and fundus had increased at the last examination at age 4 years. Albino misrouting was present at this age. In the maternal uncle (III.3, 51 years) who also suffered from congenital nystagmus there was clear macular hypoplasia and stromal focal hypopigmentation of the iris but no iris translucency or fundus hypopigmentation. Patient 3 (II.3, 79 years, maternal uncle of patient III.3) had congenital nystagmus and was highly myopic. The fundus appearance was typical for excessive myopia including macular changes. The iris did not show any translucency. Molecular genetic analysis revealed a novel 14 bp deletion of the OA1 gene at nt816 in exon 6. The mutation abolishes four amino acids (Leu 253-Ile-Ile-Cys) and covers the splice site. Nucleotides 814/815 are used as a new splice donor thus producing a frame shift in codon 252 and a new stop codon at codon 259.
CONCLUSIONS—Macular hypoplasia without clinically detectable hypopigmentation as the only sign of X linked OA1 has been reported occasionally in African-American, Japanese, and white patients. The present family shows absent hypopigmentation in two patients of a white family with a deletion in the OA1 gene. We propose a model of OA1 that allows increase of pigmentation with age. We hypothesise that macular hypoplasia in all forms of albinism depends on the extracellular DOPA level during embryogenesis, and that in OA1 postnatal normalisation of the extracellular DOPA level due to delayed distribution and membrane budding/fusion of melanosomes in melanocytes results in increasing pigmentation.



Full Text

The Full Text of this article is available as a PDF (270.8 KB).

Figure 1  .

Figure 1  

Open in a new tab

Pedigree of family 74 segregating the OA1 gene mutation.

Figure 2  .

Figure 2  

Open in a new tab

External aspect of (A) patient IV.1 at age 2.5 years and (B) patient III.3 at age 54 years. Tanning is obvious in both patients. Patient III.3 additionally has very dark hair colour.

Figure 3  .

Figure 3  

Open in a new tab

Testing of iris translucency in patient (A) IV.1 and (B) III.3, and iris pigmentation in patient III.3 (C). Patchy hypopigmentation can be seen in the iris stroma of patient III.3 but no obvious translucency can be detected compared with patient IV.1. Fundus appearance showing macular hypoplasia and varying degrees of hypopigmentation in patients IV.1 (D), III.3 (E), II.3 (F), and the carrier III.2 (G) (mother of patient IV.1).

Figure 4  .

Figure 4  

Open in a new tab

(A) Tsp509I restriction enzyme digest. The wild type sequence is cut once to produce fragments of 157 bp and 69 bp. This site is lost by the 816del14bp mutation. Lanes: (1) control, (2) patient II.3, (3) patient IV.1, (4) carrier III.2, (5) patient III.3, (6) control. (M) Marker: 100 bp ladder. (B) RT-PCR using RNA from (1) control melanocytes, (2) patient III.3 melanocytes, (3-5) preparations from a control donor eye (3) retina, (4) RPE and choroid, (5) RPE with choroid contamination. (M) Marker: 100 bp ladder. (C) Schematic showing the effect of the 816del14bp mutation on RNA splicing. The mutant gene is shown in grey.

Figure 5  .

Figure 5  

Open in a new tab

Schematic indicating maturation steps of melanosomes possibly impaired by mutated OA1. Budding of vesicles from ER and Golgi membranes is controlled by small G proteins (Ras or Rab) which may represent ligands to the GPCR OA1. Mutations in OA1 would cause a delay in budding and, therefore, vesicles with increased size. (2) The same group of G proteins controls targeting of vesicles (melanosomes) to intracellular compartments and the plasma membrane. Mutations in OA1 would cause intracellular misrouting of vesicles. (3) As a third function of a transmembrane GPCR, interaction of OA1 with an acceptor molecule on the plasma membrane can be proposed. Absent or altered OA1 would cause impaired DOPA excretion by impaired membrane fusion. An alternative way of excretion would be passive lipid mediated membrane fusion which rarely occurs spontaneously at membrane surfaces but requires more time. Any of the steps mentioned above cause impaired excretion of DOPA and even if passive membrane fusion or vesicle targeting occurs, it will not be possible to excrete sufficient amounts of DOPA in time.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Apkarian P., Shallo-Hoffmann J. VEP projections in congenital nystagmus; VEP asymmetry in albinism: a comparison study. Invest Ophthalmol Vis Sci. 1991 Aug;32(9):2653–2661. [PubMed] [Google Scholar]
  2. Bassi M. T., Schiaffino M. V., Renieri A., De Nigris F., Galli L., Bruttini M., Gebbia M., Bergen A. A., Lewis R. A., Ballabio A. Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome. Nat Genet. 1995 May;10(1):13–19. doi: 10.1038/ng0595-13. [DOI] [PubMed] [Google Scholar]
  3. Charles S. J., Green J. S., Grant J. W., Yates J. R., Moore A. T. Clinical features of affected males with X linked ocular albinism. Br J Ophthalmol. 1993 Apr;77(4):222–227. doi: 10.1136/bjo.77.4.222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Charles S. J., Moore A. T., Grant J. W., Yates J. R. Genetic counselling in X-linked ocular albinism: clinical features of the carrier state. Eye (Lond) 1992;6(Pt 1):75–79. doi: 10.1038/eye.1992.15. [DOI] [PubMed] [Google Scholar]
  5. Cortin P., Tremblay M., Lemagne J. M. X-linked ocular albinism: relative value of skin biopsy, iris transillumination and funduscopy in identifying affected males and carriers. Can J Ophthalmol. 1981 Jul;16(3):121–123. [PubMed] [Google Scholar]
  6. Ernst O. P., Meyer C. K., Marin E. P., Henklein P., Fu W. Y., Sakmar T. P., Hofmann K. P. Mutation of the fourth cytoplasmic loop of rhodopsin affects binding of transducin and peptides derived from the carboxyl-terminal sequences of transducin alpha and gamma subunits. J Biol Chem. 2000 Jan 21;275(3):1937–1943. doi: 10.1074/jbc.275.3.1937. [DOI] [PubMed] [Google Scholar]
  7. Garner A., Jay B. S. Macromelanosomes in X-linked ocular albinism. Histopathology. 1980 May;4(3):243–254. doi: 10.1111/j.1365-2559.1980.tb02919.x. [DOI] [PubMed] [Google Scholar]
  8. Horn M., Humphries P., Kunisch M., Marchese C., Apfelstedt-Sylla E., Fugi L., Zrenner E., Kenna P., Gal A., Farrar J. Deletions in exon 5 of the human rhodopsin gene causing a shift in the reading frame and autosomal dominant retinitis pigmentosa. Hum Genet. 1992 Nov;90(3):255–257. doi: 10.1007/BF00220073. [DOI] [PubMed] [Google Scholar]
  9. Ilia M., Jeffery G. Retinal mitosis is regulated by dopa, a melanin precursor that may influence the time at which cells exit the cell cycle: analysis of patterns of cell production in pigmented and albino retinae. J Comp Neurol. 1999 Mar 15;405(3):394–405. doi: 10.1002/(sici)1096-9861(19990315)405:3<394::aid-cne9>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  10. Incerti B., Cortese K., Pizzigoni A., Surace E. M., Varani S., Coppola M., Jeffery G., Seeliger M., Jaissle G., Bennett D. C. Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1. Hum Mol Genet. 2000 Nov 22;9(19):2781–2788. doi: 10.1093/hmg/9.19.2781. [DOI] [PubMed] [Google Scholar]
  11. Lam B. L., Fingert J. H., Shutt B. C., Singleton E. M., Merin L. M., Brown H. H., Sheffield V. C., Stone E. M. Clinical and molecular characterization of a family affected with X-linked ocular albinism (OA1) Ophthalmic Genet. 1997 Dec;18(4):175–184. doi: 10.3109/13816819709041432. [DOI] [PubMed] [Google Scholar]
  12. Lindquist N. G., Larsson B. S., Stjernschantz J. Increased pigmentation of iridial melanocytes in primates induced by a prostaglandin analogue. Exp Eye Res. 1999 Oct;69(4):431–436. doi: 10.1006/exer.1999.0718. [DOI] [PubMed] [Google Scholar]
  13. Lorenz B. Albinismus. Aktuelle klinische und molekulargenetische Aspekte einer wichtigen Differentialdiagnose des kongenitalen Nystagmus. Ophthalmologe. 1997 Jul;94(7):534–544. doi: 10.1007/s003470050155. [DOI] [PubMed] [Google Scholar]
  14. Lorenz B., Gampe E. Analyse von 180 Patienten mit sensorischem Defektnystagmus (SDN) und kongenitalem idiopathischen Nystagmus (CIN). Klin Monbl Augenheilkd. 2001 Jan;218(1):3–12. doi: 10.1055/s-2001-11254. [DOI] [PubMed] [Google Scholar]
  15. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. O'Donnell F. E., Jr, Green W. R., Fleischman J. A., Hambrick G. W. X-linked ocular albinism in Blacks. Ocular albinism cum pigmento. Arch Ophthalmol. 1978 Jul;96(7):1189–1192. doi: 10.1001/archopht.1978.03910060023005. [DOI] [PubMed] [Google Scholar]
  17. O'Donnell F. E., Jr, Hambrick G. W., Jr, Green W. R., Iliff W. J., Stone D. L. X-linked ocular albinism. An oculocutaneous macromelanosomal disorder. Arch Ophthalmol. 1976 Nov;94(11):1883–1892. doi: 10.1001/archopht.1976.03910040593001. [DOI] [PubMed] [Google Scholar]
  18. Restagno G., Maghtheh M., Bhattacharya S., Ferrone M., Garnerone S., Samuelly R., Carbonara A. A large deletion at the 3' end of the rhodopsin gene in an Italian family with a diffuse form of autosomal dominant retinitis pigmentosa. Hum Mol Genet. 1993 Feb;2(2):207–208. doi: 10.1093/hmg/2.2.207. [DOI] [PubMed] [Google Scholar]
  19. Schiaffino M. V., Bassi M. T., Galli L., Renieri A., Bruttini M., De Nigris F., Bergen A. A., Charles S. J., Yates J. R., Meindl A. Analysis of the OA1 gene reveals mutations in only one-third of patients with X-linked ocular albinism. Hum Mol Genet. 1995 Dec;4(12):2319–2325. doi: 10.1093/hmg/4.12.2319. [DOI] [PubMed] [Google Scholar]
  20. Schiaffino M. V., d'Addio M., Alloni A., Baschirotto C., Valetti C., Cortese K., Puri C., Bassi M. T., Colla C., De Luca M. Ocular albinism: evidence for a defect in an intracellular signal transduction system. Nat Genet. 1999 Sep;23(1):108–112. doi: 10.1038/12715. [DOI] [PubMed] [Google Scholar]
  21. Shapiro M. B., Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987 Sep 11;15(17):7155–7174. doi: 10.1093/nar/15.17.7155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Shiono T., Tsunoda M., Chida Y., Nakazawa M., Tamai M. X linked ocular albinism in Japanese patients. Br J Ophthalmol. 1995 Feb;79(2):139–143. doi: 10.1136/bjo.79.2.139. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The British Journal of Ophthalmology are provided here courtesy of BMJ Publishing Group

RESOURCES