TY - JOUR
T1 - CRB1 heterozygotes with regional retinal dysfunction
T2 - Implications for genetic testing of leber congenital amaurosis
AU - Yzer, Suzanne
AU - Fishman, Gerald A.
AU - Racine, Julie
AU - Al-Zuhaibi, Sana
AU - Chakor, Hadi
AU - Dorfman, Attison
AU - Szlyk, Janet
AU - Lachapelle, Pierre
AU - Van Den Born, L. Ingeborgh
AU - Allikmets, Rando
AU - Lopez, Irma
AU - Cremers, Frans P.M.
AU - Koenekoop, Robert K.
PY - 2006/9
Y1 - 2006/9
N2 - 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.
AB - 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.
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U2 - 10.1167/iovs.05-1637
DO - 10.1167/iovs.05-1637
M3 - Article
C2 - 16936081
AN - SCOPUS:33749133442
SN - 0146-0404
VL - 47
SP - 3736
EP - 3744
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 9
ER -