CRB1 heterozygotes with regional retinal dysfunction: Implications for genetic testing of leber congenital amaurosis

Suzanne Yzer, Gerald A. Fishman, Julie Racine, Sana Al-Zuhaibi, Hadi Chakor, Attison Dorfman, Janet Szlyk, Pierre Lachapelle, L. Ingeborgh Van Den Born, Rando Allikmets, Irma Lopez, Frans P M Cremers, Robert K. Koenekoop

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

PURPOSE. To test human CRB1 heterozygotes for possible clinical or functional retinal changes and to evaluate whether a patient with Leber congenital amaurosis (LCA.) with CRB1 mutations not consistent with previously described CRB1 phenotypes carried a modifier allele in another LCA gene. METHODS. Seven unrelated heterozygous carriers of CRB1 mutations underwent phenotyping by full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing (standard full-field electroretinography [ERG] and multifocal ERG). For genotyping of the LCA patients and their parents, denaturing high-performance liquid chromatography (dHPLC) analyses were performed, followed by sequence analysis of CRB1, followed by sequence analysis of the AIPL1 and CRX genes to identify a putative modifier effect in a patient with an atypical CRB1 phenotype. RESULTS. Reduced full-field ERG b-wave amplitudes were observed with scotopic -2 dB flash (140 λV; P < 0.05), normal full-field cone ERGs, and significant regional retinal dysfunction on mfERG in five of seven carriers of CRB1 mutations. A known AIPL1 mutation (p. R302L) was identified as a potential modifier allele in a patient with LCA carrying two CRB1 mutations and with a prominent maculopathy. CONCLUSIONS. In human heterozygotes of CRB1 mutations (parents of offspring with LCA), distinctive regional retinal dysfunctions were found by multifocal ERG measurements that were consistent with the focal histologic abnormalities reported for the two CRB1 knockout mice models. This phenotypic rinding may identify CRB1 carriers and point to the causal gene defect in affected LCA offspring, significantly facilitating the molecular diagnostic process. Evidence suggests a modifier allele in AlPL1 in a patient with LCA with prominent atrophic macular lesions and homozygous defects in CRB1.

Original languageEnglish
Pages (from-to)3736-3744
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume47
Issue number9
DOIs
Publication statusPublished - Sep 2006

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'CRB1 heterozygotes with regional retinal dysfunction: Implications for genetic testing of leber congenital amaurosis'. Together they form a unique fingerprint.

  • Cite this

    Yzer, S., Fishman, G. A., Racine, J., Al-Zuhaibi, S., Chakor, H., Dorfman, A., Szlyk, J., Lachapelle, P., Van Den Born, L. I., Allikmets, R., Lopez, I., Cremers, F. P. M., & Koenekoop, R. K. (2006). CRB1 heterozygotes with regional retinal dysfunction: Implications for genetic testing of leber congenital amaurosis. Investigative Ophthalmology and Visual Science, 47(9), 3736-3744. https://doi.org/10.1167/iovs.05-1637