Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Nov;21(11):1266-71.
doi: 10.1038/ejhg.2013.23. Epub 2013 Feb 27.

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

Frida Jonsson  1 , Marie S Burstedt, Ola Sandgren, Anna Norberg, Irina Golovleva
Affiliations

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

Frida Jonsson et al. Eur J Hum Genet. 2013 Nov.

Abstract

This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Pedigree of the Swedish family segregating CRB1 and ABCA4 mutations. (a) DNA from index patient VI:2 (marked by an arrow) and V:4 were used for targeted mutation screening (APEX). Affected individuals are shown in shaded red or blue and healthy subjects are shown as open circles for females and squares for males. CRB1 and ABCA4 mutant alleles corresponding LCA and STGD1 phenotypes are drawn in red and blue, respectively. * denotes that DNA was not available. (b) Segregation analysis of a novel CRB1 c.2557C>T (p.Q853X) mutation in the Swedish family was carried out by PCR-restriction fragment length polymorphism analysis of the CRB1 exon 7. The 472-bp-long PCR products amplified according to the conditions described in ‘Materials and Methods' were digested with DdeI endonuclease and results were visualised on 2% agarose gel (SeaKem, ME Agarose, Lonza, Basel, Switzeland) by GelStar Nuclear Acid Staining (Cambrex, Bio Science Rockland Inc, Rockland, ME, USA). c.2557C>T mutation abolishes DdeI restriction site. LCA cases are indicated in red and STGD1 in blue.
Figure 2
Figure 2
Fundus appearance in patients with CRB1 and ABCA4 mutations. (a) LCA patient, VI:2, 43-year-old woman with LCA. Peripheral pigmentary changes with extensive macular atrophy and drusen of the optic disc are shown. (b) STGD1 patient,V:4, 56-year-old man. An extensive macular atrophy with pigmentation is shown; the atrophy is extending into the peripheral parts of the retina. (c) STGD1 patient 41, VI:10, 25-year-old woman. Central retinal atrophy of the macula with hyperpigmentations and dispersed yellowish flecks of the posterior pole are visible.
Figure 3
Figure 3
CRB1 and ABCA4 mutations causing LCA and STGD1 in the Swedish family. Sequence analysis demonstrating sequence variants CRB1 c.2557C>T (a), reverse sequence), ABCA4 c.5461-10T>C (b), reverse sequence) and ABCA4 c.4773+3A>G (c), forward sequence). The upper images show wild-type sequences, the middle images show heterozygous mutations and low images show homozygous mutations. Mutations positions are marked in black.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Chung DC, Traboulsi EI. Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J AAPOS. 2009;13:587–592. - PubMed
    1. Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat. 2004;23:306–317. - PubMed
    1. Senechal A, Humbert G, Surget MO, et al. Screening genes of the retinoid metabolism: novel LRAT mutation in leber congenital amaurosis. Am J Ophthalmol. 2006;142:702–704. - PubMed
    1. Sergouniotis PI, Davidson AE, Mackay DS, et al. Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis. Am J Hum Genet. 2011;89:183–190. - PMC - PubMed
    1. Friedman JS, Chang B, Kannabiran C, et al. Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet. 2006;79:1059–1070. - PMC - PubMed

Publication types

MeSH terms

-