Infantile and childhood retinal blindness: A molecular perspective (The Franceschetti Lecture)

  title={Infantile and childhood retinal blindness: A molecular perspective (The Franceschetti Lecture)},
  author={Richard G. Weleber},
  journal={Ophthalmic Genetics},
  pages={71 - 97}
  • R. Weleber
  • Published 1 January 2002
  • Medicine, Biology
  • Ophthalmic Genetics
Much progress has been made in the past five years in the understanding of Leber congenital amaurosis (LCA) and allied early-onset retinal dystrophies, various forms of stationary sensory retinal blindness, and genes that are involved in the development of the retina. Uncomplicated Leber congenital amaurosis has been associated with mutations of six genes: GUCY2D (encoding RetGC-1) at 17p13.1, RPE65 at 1q31, CRX at 19q13.3, AIPLI at 17p13.1, CRB1 at 1q31-3, and RPGRIP at 14q11. A similar early… 

Leber Congenital Amaurosis/Early-Onset Retinal Dystrophy in Japanese Population

The evidence on the correlations between the clinical features of Leber congenital amaurosis/early-onset retinal dystrophy and the causative genes is summarized and the clinical characteristics of representative cases for each causative gene are presented.

CRB1: One Gene, Many Phenotypes

In CRB1-disease, it is essential to diagnose the specific disease-causing gene for the disease as genetic therapy has progressed considerably in the last few years and might be applicable.

NMNAT 1 Mutations Cause Leber Congenital Amaurosis

The first to link an NMNAT isoform to disease and indicate that NMNAT1 mutations cause LCA are reported, using whole exome sequencing in a large consanguineous Falk et al.

NMNAT1 mutations cause Leber congenital amaurosis

Results indicate that NMNAT1 mutations cause LCA, the first to link an NMNAT isoform to disease in humans and indicate that this mutation segregated with disease in the kindred, including in three other children with LCA.

NR2E3 mutations in enhanced S‐cone sensitivity syndrome (ESCS), Goldmann‐Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP)

The high variability of clinical phenotypes observed in patients affected by NR2E3‐linked retinal degenerations may be caused by different disease mechanisms, including absence of DNA‐binding, altered interactions with transcriptional coregulators, and differential activity of modifier genes.



Retinal–specific guanylate cyclase gene mutations in Leber's congenital amaurosis

Two missense mutations (F589S) and two frameshift mutations (nt 460 del C, nt 693 del C) of the retinal guanylate cyclase gene in four unrelated LCA1 probands of North African ancestry are reported and ascribe LCA 1 to an impaired production of cGMP in the retina, with permanent closure of cGsMP-gated cation channels.

Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis

A new photoreceptor/pineal-expressed gene, AIPL1 (encoding aryl-hydrocarbon interacting protein-like 1), is described, that maps within the LCA4 candidate region and whose protein contains three tetratricopeptide motifs, consistent with nuclear transport or chaperone activity.

Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene.

It is suggested that CRB1 mutations are a frequent cause of LCA and are strongly associated with the development of Coats-like exudative vasculopathy in patients with RP.

Mutations in RPE65 cause autosomal recessive childhood–onset severe retinal dystrophy

The analysis of RPE65 in a collection of about 100 unselected retinal-dystrophy patients of different ethnic origin revealed five that are likely to be pathogenic mutations, including a missense mutation, two point mutations affecting splicing and two small re-arrangements on a total of nine alleles of five patients with arCSRD.

Prevalence of AIPL1 mutations in inherited retinal degenerative disease.

The results suggest that AIPL1 mutations cause approximately 7% of LCA worldwide and may cause dominant retinopathy, which is the most severe form of inherited retinal dystrophy.

A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene.

Four CRX mutations in families with clinical diagnoses of autosomal dominant cone-rod dystrophy, late-onset dominant retinitis pigmentosa, or dominant congenital Leber amaurosis are identified, and four additional benign sequence variants are identified.

Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function.

Data suggest that the R90W mutation results in a CRX protein with reduced DNA binding and transcriptional regulatory activity and that the subsequent changes in photoreceptor gene expression lead to the very early onset severe visual impairment in LCA.

Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis.

All 14 exons of this gene were examined in 147 unrelated patients with autosomal recessive retinitis pigmentosa, in 15 patients with isolate RP, and in 45 patients with Leber congenital amaurosis, and mutations in the RPE65 gene appear to account for approximately 2% of cases of recessive RP and approximately 16% of Cases of LCA.

Autosomal dominant retinal degeneration and bone loss in patients with a 12-bp deletion in the CRX gene.

This large deletion of the CRX gene is associated with a severe form of autosomal dominant retinal degeneration and may reflect the abnormal influence of mutant CRX on both retinal and pineal development.