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A complete, homozygous CRX deletion causing nullizygosity is a new genetic mechanism for Leber congenital amaurosis.

ABSTRACT: CRX is a transcription factor required for activating the expression of many photoreceptor-neuron genes. CRX may be mutated in three forms of human blindness; Leber congenital amaurosis (LCA), cone-rod degeneration (CRD) and retinitis pigmentosa (RP). The pathogenic mechanism in most cases is likely dominant negative, with gain of function. We report a novel, complete homozygous CRX deletion in LCA. We identified a Lebanese family with 3 affected LCA cases. The proband was sequenced by NGS. Quantitative PCR, array comparative genomic hybridization, and long range PCR were performed. Full eye examinations, OCT and photography were performed. We identified a homozygous 56,000?bp deletion of CRX, which co-segregates and is heterozygous in four parents, who report normal vision. The blind children with LCA manifest severe retinal degeneration, a phenotype typical for CRX and LCA. We hypothesized that a single copy of CRX (haplo-insufficiency) in the causes mild abnormal foveal development, but not LCA. Two parents had significant inner and outer foveal and photoreceptor abnormalities. This is the first reported case of a homozygous, complete CRX deletion. Nullizygosity of CRX thus causes LCA while haplo-insufficiency of CRX causes abnormal foveal development, but not LCA. Our data suggest a new disease mechanism for CRX.

SUBMITTER: Ibrahim MT

PROVIDER: S-EPMC5864841 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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A complete, homozygous CRX deletion causing nullizygosity is a new genetic mechanism for Leber congenital amaurosis.

Ibrahim M T MT Alarcon-Martinez T T Lopez I I Fajardo N N Chiang J J Koenekoop R K RK

Scientific reports 20180322 1

CRX is a transcription factor required for activating the expression of many photoreceptor-neuron genes. CRX may be mutated in three forms of human blindness; Leber congenital amaurosis (LCA), cone-rod degeneration (CRD) and retinitis pigmentosa (RP). The pathogenic mechanism in most cases is likely dominant negative, with gain of function. We report a novel, complete homozygous CRX deletion in LCA. We identified a Lebanese family with 3 affected LCA cases. The proband was sequenced by NGS. Quan ...[more]

PMID: 29568065

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Project description:PurposeLeber congenital amaurosis (LCA) is one of the most common causes of hereditary blindness in infants. To date, mutations in 13 known genes and at two other loci have been implicated in LCA causation. An examination of the known genes highlights several processes which, when defective, cause LCA, including photoreceptor development and maintenance, phototransduction, vitamin A metabolism, and protein trafficking. In addition, it has been known for some time that defects in sensory cilia can cause syndromes involving hereditary blindness. More recently evidence has come to light that non-syndromic LCA can also be a "ciliopathy."MethodsHere we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene. Homozygosity mapping was done using Affymetrix 10K Xba I Gene Chip and a 24.5cM region on chromosome 6 (6q12- q16.3) was identified to be significantly homozygous. The LCA5 gene on this region was sequenced and cDNA sequencing also done to characterize the mutation.ResultsA c.955G>A missense mutation in the last base of exon 6 causing disruption of the splice donor site was identified in both the affected sibs. Since there is a second consensus splice donor sequence 5 bp into the adjacent intron, this mutation results in a transcript with a 5 bp insertion of intronic sequence, leading to a frameshift and premature truncation.ConclusionsWe report a missense mutation functionally altering the splice donor site and leading to a truncated protein. This is the second report of LCA5 mutations causing LCA. It may also be significant that one affected child died at eleven months of age due to asphyxia during sleep. To date the only phenotype unambiguously associated with mutations in this gene is LCA. However the LCA5 gene is known to be expressed in nasopharynx, trachea and lungs and was originally identified in the proteome of bronchial epithelium ciliary axonemes. The cause of death in this child may therefore imply that LCA5 mutations can in fact cause a wider spectrum of phenotypes including respiratory disease.

Dataset Information

A complete, homozygous CRX deletion causing nullizygosity is a new genetic mechanism for Leber congenital amaurosis.

Publications

A complete, homozygous CRX deletion causing nullizygosity is a new genetic mechanism for Leber congenital amaurosis.

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