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A null mutation in CABP4 causes Leber's congenital amaurosis-like phenotype.

ABSTRACT: PURPOSE: To describe the finding of a novel calcium binding protein 4 (CABP4) mutation in a family with Leber congenital amaurosis (LCA) phenotype. METHODS: Homozygosity mapping was performed in a consanguineous family with four affected members originally referred as cases of LCA. Detailed electroretinographic recordings were obtained. RESULTS: A novel homozygous single base-pair insertion was identified in all four siblings. The patients had an LCA-like phenotype, including either flat or greatly diminished electroretinographic activity. CONCLUSIONS: This report significantly expands on the phenotype associated with calcium binding protein 4 mutations, which has so far been limited to congenital stationary night blindness, and further demonstrates how molecular data often blur the boundaries between what are believed to be clinically distinct retinal disorders.

SUBMITTER: Aldahmesh MA

PROVIDER: S-EPMC2820108 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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A null mutation in CABP4 causes Leber's congenital amaurosis-like phenotype.

Aldahmesh Mohammed A MA Al-Owain Mohammed M Alqahtani Faisal F Hazzaa Salwa S Alkuraya Fowzan S FS

Molecular vision 20100210

<h4>Purpose</h4>To describe the finding of a novel calcium binding protein 4 (CABP4) mutation in a family with Leber congenital amaurosis (LCA) phenotype.<h4>Methods</h4>Homozygosity mapping was performed in a consanguineous family with four affected members originally referred as cases of LCA. Detailed electroretinographic recordings were obtained.<h4>Results</h4>A novel homozygous single base-pair insertion was identified in all four siblings. The patients had an LCA-like phenotype, including ...[more]

PMID: 20157620

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Project description:Pathogenesis in the Rpe65(-/-) mouse model of Leber's congenital amaurosis (LCA) is characterized by a slow and progressive degeneration of the rod photoreceptors. On the opposite, cones degenerate rapidly at early ages. Retinal degeneration in Rpe65(-/-) mice, showing a null mutation in the gene encoding the retinal pigment epithelium 65-kDa protein (Rpe65), was previously reported to depend on continuous activation of a residual transduction cascade by unliganded opsin. However, the mechanisms of apoptotic signals triggered by abnormal phototransduction remain elusive. We previously reported that activation of a Bcl-2-dependent pathway was associated with apoptosis of rod photoreceptors in Rpe65(-/-) mice during the course of the disease. In this study we first assessed whether activation of Bcl-2-mediated apoptotic pathway was dependent on constitutive activation of the visual cascade through opsin apoprotein. We then challenged the direct role of pro-apoptotic Bax protein in triggering apoptosis of rod and cone photoreceptors.Quantitative PCR analysis showed that increased expression of pro-apoptotic Bax and decreased level of anti-apoptotic Bcl-2 were restored in Rpe65(-/-)/Gnat1(-/-) mice lacking the Gnat1 gene encoding rod transducin. Moreover, photoreceptor apoptosis was prevented as assessed by TUNEL assay. These data indicate that abnormal activity of opsin apoprotein induces retinal cell apoptosis through the Bcl-2-mediated pathway. Following immunohistological and real-time PCR analyses, we further observed that decreased expression of rod genes in Rpe65-deficient mice was rescued in Rpe65(-/-)/Bax(-/-) mice. Histological and TUNEL studies confirmed that rod cell demise and apoptosis in diseased Rpe65(-/-) mice were dependent on Bax-induced pathway. Surprisingly, early loss of cones was not prevented in Rpe65(-/-)/Bax(-/-) mice, indicating that pro-apoptotic Bax was not involved in the pathogenesis of cone cell death in Rpe65-deficient mice.This is the first report, to our knowledge, that a single genetic mutation can trigger two independent apoptotic pathways in rod and cone photoreceptors in Rpe65-dependent LCA disease. These results highlight the necessity to investigate and understand the specific death signaling pathways committed in rods and cones to develop effective therapeutic approaches to treat RP diseases.

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A null mutation in CABP4 causes Leber's congenital amaurosis-like phenotype.

Publications

A null mutation in CABP4 causes Leber's congenital amaurosis-like phenotype.

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