Mutational analysis and clinical correlation in Leber congenital amaurosis

Dharmaraj, Sharola; Silva, Eduardo; Piña, Ana Luisa; Li, Ying Ying; Yang, Jun-Ming; Carter, R. Colin; Loyer, Magali; Elhilali, Hala; Traboulsi, Elias I.; Sundin, Olof; Zhu, Daocheng; Koenekoop, Robert K.; Maumenee, Irene H.

doi:10.1076/1381-6810(200009)2131-zft135

Cited by 73 publications

(54 citation statements)

References 24 publications

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“…However, the deletion was not found in our control population. We also identified GUCY2D mutations in ARRP patients 25855 and 8432 (p.Pro701Ser) 34 and in LCA patient 26669 (p.Arg768Trp). 35 The second new mutation was a deletion causing a frameshift in RPGRIP1:c1614_1623del, p.Glu538Glufs2 in IRP patient 25140.…”

Section: Mutationsmentioning

confidence: 72%

Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa

Booij

Florijn²,

Brink³

et al. 2005

Journal of Medical Genetics

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Objective: To identify mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. Methods: Mutation analysis was carried out in a group of 35 unrelated patients with juvenile autosomal recessive retinitis pigmentosa (ARRP), Leber's congenital amaurosis (LCA), or juvenile isolated retinitis pigmentosa (IRP), by denaturing high performance liquid chromatography followed by direct sequencing.Results: All three groups of patients showed typical combinations of eye signs associated with retinitis pigmentosa: pale optic discs, narrow arterioles, pigmentary changes, and nystagmus. Mutations were found in 34% of patients: in CRB1 (11%), GUCY2D (11%), RPE65 (6%), and RPGRIP1 (6%). Nine mutations are reported, including a new combination of two mutations in CRB1, and new mutations in GUCY2D and RPGRIP1. The new GUCY2D mutation (c.3283delC, p.Pro1069ArgfsX37) is the first pathological sequence change reported in the intracellular C-terminal domain of GUCY2D, and did not lead to the commonly associated LCA, but to a juvenile retinitis pigmentosa phenotype. The polymorphic nature of three previously described (pathological) sequence changes in AIPL1, CRB1, and RPGRIP1 was established. Seven new polymorphic changes, useful for further association studies, were found. Conclusions: New and previously described sequence changes were detected in retinitis pigmentosa in CRB1, GUCY2D, and RPGRIP1; and in LCA patients in CRB1, GUCY2D, and RPE65. These data, combined with previous reports, suggest that LCA and juvenile ARRP are closely related and belong to a continuous spectrum of juvenile retinitis pigmentosa.

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Section: Mutationsmentioning

confidence: 72%

Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa

Booij

Florijn²,

Brink³

et al. 2005

Journal of Medical Genetics

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“…CRX is the only gene associated with all three diseases [22] [23] [26] [43], demonstrating its central role in rod and cone integrity. However, null mutations in CRX may not be responsible for severe dominant disease.…”

Section: Introductionmentioning

confidence: 99%

Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

et al. 2014

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Cone-rod homeobox (CRX) protein is a “paired-like” homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD) and Leber Congenital Amaurosis (LCA), with variable severity. Heterozygous Crx Knock-Out (KO) mice (“+/−”) have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN) mouse models: CrxE168d2 (“E168d2”) and CrxR90W (“R90W”). E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 (“E168d2/+”) but not R90W (“R90W/+”) mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/− mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX[E168d2] and CRX[R90W] proteins fail to activate transcription in vitro, but CRX[E168d2] interferes more strongly with the function of wild type (WT) CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of novel therapeutic approaches for different forms of CRX-associated disease.

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“…The clinical features of LCA include blindness or severe vision impairment, congenital nystagmus, amaurotic pupils, and reduced or absence of signal in electroretinogram (ERG) [Franceschetti and Dieterle, 1954]. It is estimated to affect one in every 30,000~80,000 individuals and represents 5% of all retinal dystrophies [Dharmaraj et al, 2000; Kaplan et al, 1990; Leber, 1869; Stone, 2007]. …”

Section: Introductionmentioning

confidence: 99%

Whole-exome sequencing identifiesALMS1, IQCB1, CNGA3, andMYO7Amutations in patients with leber congenital amaurosis

Wang

Cao

et al. 2011

Hum. Mutat.

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It has been well documented that mutations in the same retinal disease gene can result in different clinical phenotypes due to difference in the mutant allele and/or genetic background. To evaluate this, a set of consanguineous patient families with Leber congenital amaurosis (LCA) that do not carry mutations in known LCA disease genes was characterized through homozygosity mapping followed by targeted exon/whole-exome sequencing to identify genetic variations. Among these families, a total of five putative disease-causing mutations, including four novel alleles, were found for six families. These five mutations are located in four genes, ALMS1, IQCB1, CNGA3, and MYO7A. Therefore, in our LCA collection from Saudi Arabia, three of the 37 unassigned families carry mutations in retinal disease genes ALMS1, CNGA3, and MYO7A, which have not been previously associated with LCA, and 3 of the 37 carry novel mutations in IQCB1, which has been recently associated with LCA. Together with other reports, our results emphasize that the molecular heterogeneity underlying LCA, and likely other retinal diseases, may be highly complex. Thus, to obtain accurate diagnosis and gain a complete picture of the disease, it is essential to sequence a larger set of retinal disease genes and combine the clinical phenotype with molecular diagnosis.

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Mutational analysis and clinical correlation in Leber congenital amaurosis

Abstract: This study suggests that molecular diagnosis of Leber congenital amaurosis could provide important information concerning prognosis and course of treatment.

Cited by 73 publications

References 24 publications

Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa

Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa

Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

Whole-exome sequencing identifiesALMS1, IQCB1, CNGA3, andMYO7Amutations in patients with leber congenital amaurosis

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