A Comprehensive Survey of Sequence Variation in the ABCA4 (ABCR) Gene in Stargardt Disease and Age-Related Macular Degeneration

Rivera, Andrea; White, Karen L.; Stöhr, Heidi; Steiner, Klaus; Hemmrich, N; Grimm, T; Jurklies, Bernhard; Lorenz, Birgit; Scholl, Hendrik P. N.; Apfelstedt-Sylla, Eckart; Weber, Bernhard H. F.

doi:10.1086/303090

Cited by 282 publications

(245 citation statements)

References 32 publications

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“…These data are in agreement with the results of earlier investigations in the Italian population and with other studies in a sizeable series of patients. 9,12,25 We identified 28 novel ABCR mutations, confirming and further highlighting the high heterogeneity of the ABCR gene in STGD. The frequent report of novel mutations is probably related to the enormous number of exons in the ABCR gene, which favours rearrangement in the DNA sequence.…”

Section: Discussionsupporting

confidence: 65%

“…8 Several series of mutation analyses have confirmed that homozygous and compound heterozygous mutations in ABCR are responsible for recessive STGD. [9][10][11][12][13] ABCR has also been singled out as a possible cause of other diseases with similar clinical macular abnormalities. Gene mutations have been observed in families manifesting cone-rod dystrophy, 14 retinitis pigmentosa, 15 and age-related macular degeneration (AMD).…”

Section: Introductionmentioning

confidence: 99%

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Novel mutations in of the ABCR gene in italian patients with Stargardt disease

Passerini

Sodi

Giambene

et al. 2009

Eye

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Purpose: Stargardt disease (STGD) is the most prevalent juvenile macular dystrophy, and it has been associated with mutations in the ABCR gene, encoding a photoreceptor-specific transport protein. In this study, we determined the mutation spectrum in the ABCR gene in a group of Italian STGD patients. Methods: The DNA samples of 71 Italian patients (from 62 independent pedigrees), affected with autosomal recessive STGD, were analysed for mutations in all 50 exons of the ABCR gene by the DHPLC approach (with optimization of the DHPLC conditions for mutation analysis) and direct sequencing techniques. Results: In our group of STGD patients, 71 mutations were identified in 68 patients with a detection rate of 95.7%. Forty-three mutations had been already reported in the literature, whereas 28 mutations had not been previously described and were not detected in 150 unaffected control individuals of Italian origin. Missense mutations represented the most frequent finding (59.2%); G1961E was the most common mutation and it was associated with phenotypes in various degrees of severity. Conclusions: Some novel mutations in the ABCR gene were reported in a group of Italian STGD patients confirming the extensive allelic heterogeneity of this geneFprobably related to the vast number of exons that favours rearrangements in the DNA sequence.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Novel mutations in of the ABCR gene in italian patients with Stargardt disease

Passerini

Sodi

Giambene

et al. 2009

Eye

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“…However, the assumption that these mutations are disease-causing is supported by the hypothesis that the missense variants p.L252F and p.V415A (Table 2: Patients 19-1 and 19-2), as well as the mutations p.S1049A and p.S1403R (Table 2: Patient 36), might be located in closed proximity in the native MRP6 and therefore the resulting amino acid variants are thought to interfere with each other. Furthermore, the occurrence of 2 putative mutations on one allele has also been reported for other ABC transporters (Rivera et al, 2000;Webster et al, 2001). Family 25 shows a pseudo-dominant inheritance with PXE-affected family members in two subsequent generations (Fig.…”

Section: Novel Pxe Mutationsmentioning

confidence: 78%

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

et al. 2006

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Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by calcification of elastic fibers in dermal, ocular, and cardiovascular tissues. Recently, ABCC6 mutations were identified as causing PXE. In this follow-up study we report the investigation of 61German PXE patients from 53 families, hitherto the largest cohort of German PXE patients screened for the complete ABCC6 gene. In addition, we characterized the proximal ABCC6 promoter of PXE patients according to mutation. In this study we identified 32 disease-causing ABCC6 variants, which had been described previously by us and others, and 10 novel mutations (eight missense mutations and two splice site alterations). The mutation detection rate among index patients was 87.7%. Frequent alterations were the PXE-mutations p.R1141X, Ex23,_Ex29del, and c.2787+1G>T. In the ABCC6 promoter we found the polymorphisms c.-127C>T, c.-132C>T, and c.-219A>C. The difference in the c.-219A>C frequencies between PXE patients and controls were determined as statistically significant. Interestingly, c.-219A>C is located in a transcriptional activator sequence of the ABCC6 promoter and occurred in a binding site for a transcriptional repressor, predominantly found in genes that participate in lipid metabolism. Obtaining these genetic data signifies our contribution to elucidating the pathogenetics of PXE.

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“…34 In another study, the variant was found in 27 of 518 STGD1 patients compared with 1 of 316 clinically matched control individuals. 33 It is to be noticed that another affected member (VI:10) in the same family was homozygous for the c.5461-10T4C mutation. None of our healthy controls carried the c.5461-10T4C mutation, in line with previous observations of different population carrier frequencies.…”

Section: Discussionmentioning

confidence: 98%

“…30,31 The c.5461-10T4C mutation was first reported by Maugeri et al, 32 although its function is still not resolved. The functional consequence of c.5461-10T4C was accessed in a study with the Exon Trapping System by Rivera et al, 33 who classified this nucleotide change as a rare sequence variant, as only correctly spliced exon was detected. The majority of STGD1 patients are compound heterozygotes, with our patient V:4 not being an exception, representing one of multiple cases with the c.5461-10T4C mutation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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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.2557C4T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T4C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773 þ 3A4G. 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.

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A Comprehensive Survey of Sequence Variation in the ABCA4 (ABCR) Gene in Stargardt Disease and Age-Related Macular Degeneration

Cited by 282 publications

References 32 publications

Novel mutations in of the ABCR gene in italian patients with Stargardt disease

Novel mutations in of the ABCR gene in italian patients with Stargardt disease

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

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

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