Limits...
Novel ABCA4 compound heterozygous mutations cause severe progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease.

Xi Q, Li L, Traboulsi EI, Wang QK - Mol. Vis. (2009)

Bottom Line: Unaffected family members either did not carry either or had only one of the two mutations.We have identified two novel ABCA4 mutations, c.655A>T and c.5312+3A>T.These results expand the wide range of clinical manifestations of ABCA4 mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA.

ABSTRACT

Purpose: To identify the gene causing a severe form of progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease and to characterize clinical features in a large American family.

Methods: We characterized an American family who had an unusual retinal dystrophy with clinical features of Stargardt disease and severe progressive cone-rod dystrophy. Family members underwent complete ocular examinations with evaluation of visual acuity, visual fields, fundus examination, fluorescein angiography, and electroretinography. Genome-wide linkage analysis of the family was performed using 408 microsatellite markers spanning the entire human genome. Direct DNA sequence analysis was used for mutational analysis of the ABCA4 gene in all exons and exon-intron boundary regions and for testing cosegregation of the mutations with the disease in the family. DNA sequence analysis was used to determine the presence of the mutations in 200 unrelated controls.

Results: The proband presented with a clinical phenotype that was initially compatible with Stargardt disease, only to progress to a severe cone-rod dystrophy over the course of a few years. The disease-causing gene in the family was linked to the ABCA4 locus on chromosomal 1p22. One novel mutation, c.655A>T, was identified in exon 6 and another novel splicing mutation, c.5312+3A>T, was identified in intron 37 of ABCA4. The mutations were not present in 200 controls. The two affected sisters in this pedigree were compound heterozygotes for the mutations. Unaffected family members either did not carry either or had only one of the two mutations.

Conclusions: We have identified two novel ABCA4 mutations, c.655A>T and c.5312+3A>T. When present as a compound heterozygous state, the mutations cause a phenotype of retinal dystrophy that initially manifests as Stargardt disease and slowly progresses to a severe cone-rod dystrophy. These results expand the wide range of clinical manifestations of ABCA4 mutations.

Show MeSH

Related in: MedlinePlus

Cosegregation of two novel ABCA4 mutations with the disease in the family. Sequence analysis on mutations c.655A>T and c.5312+3A>T were done on every family member. Both mutations cosegregated with the disease within the family. Both affected sisters inherited the c.655A>T mutant allele from their father and the c.5312+3A>T mutant allele from their mother. Normal siblings either carried both widetype alleles (II-2, 6, 8, 9) or only one mutant allele (II-3, 5, 7, 10).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2665199&req=5

f4: Cosegregation of two novel ABCA4 mutations with the disease in the family. Sequence analysis on mutations c.655A>T and c.5312+3A>T were done on every family member. Both mutations cosegregated with the disease within the family. Both affected sisters inherited the c.655A>T mutant allele from their father and the c.5312+3A>T mutant allele from their mother. Normal siblings either carried both widetype alleles (II-2, 6, 8, 9) or only one mutant allele (II-3, 5, 7, 10).

Mentions: Direct DNA sequence analysis was used to determine whether the mutations cosegregate with the disease in the family. As shown in Figure 4, only the two affected siblings carried both mutations, c.655A>T from the father and c.5312+3A>T from the mother. Thus, the affected individuals are compound heterozygotes for both mutations. However, the normal family members carried only one or neither of the two mutations. These two mutations were not found in 200 unrelated controls by direct DNA sequence analysis.


Novel ABCA4 compound heterozygous mutations cause severe progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease.

Xi Q, Li L, Traboulsi EI, Wang QK - Mol. Vis. (2009)

Cosegregation of two novel ABCA4 mutations with the disease in the family. Sequence analysis on mutations c.655A>T and c.5312+3A>T were done on every family member. Both mutations cosegregated with the disease within the family. Both affected sisters inherited the c.655A>T mutant allele from their father and the c.5312+3A>T mutant allele from their mother. Normal siblings either carried both widetype alleles (II-2, 6, 8, 9) or only one mutant allele (II-3, 5, 7, 10).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2665199&req=5

f4: Cosegregation of two novel ABCA4 mutations with the disease in the family. Sequence analysis on mutations c.655A>T and c.5312+3A>T were done on every family member. Both mutations cosegregated with the disease within the family. Both affected sisters inherited the c.655A>T mutant allele from their father and the c.5312+3A>T mutant allele from their mother. Normal siblings either carried both widetype alleles (II-2, 6, 8, 9) or only one mutant allele (II-3, 5, 7, 10).
Mentions: Direct DNA sequence analysis was used to determine whether the mutations cosegregate with the disease in the family. As shown in Figure 4, only the two affected siblings carried both mutations, c.655A>T from the father and c.5312+3A>T from the mother. Thus, the affected individuals are compound heterozygotes for both mutations. However, the normal family members carried only one or neither of the two mutations. These two mutations were not found in 200 unrelated controls by direct DNA sequence analysis.

Bottom Line: Unaffected family members either did not carry either or had only one of the two mutations.We have identified two novel ABCA4 mutations, c.655A>T and c.5312+3A>T.These results expand the wide range of clinical manifestations of ABCA4 mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA.

ABSTRACT

Purpose: To identify the gene causing a severe form of progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease and to characterize clinical features in a large American family.

Methods: We characterized an American family who had an unusual retinal dystrophy with clinical features of Stargardt disease and severe progressive cone-rod dystrophy. Family members underwent complete ocular examinations with evaluation of visual acuity, visual fields, fundus examination, fluorescein angiography, and electroretinography. Genome-wide linkage analysis of the family was performed using 408 microsatellite markers spanning the entire human genome. Direct DNA sequence analysis was used for mutational analysis of the ABCA4 gene in all exons and exon-intron boundary regions and for testing cosegregation of the mutations with the disease in the family. DNA sequence analysis was used to determine the presence of the mutations in 200 unrelated controls.

Results: The proband presented with a clinical phenotype that was initially compatible with Stargardt disease, only to progress to a severe cone-rod dystrophy over the course of a few years. The disease-causing gene in the family was linked to the ABCA4 locus on chromosomal 1p22. One novel mutation, c.655A>T, was identified in exon 6 and another novel splicing mutation, c.5312+3A>T, was identified in intron 37 of ABCA4. The mutations were not present in 200 controls. The two affected sisters in this pedigree were compound heterozygotes for the mutations. Unaffected family members either did not carry either or had only one of the two mutations.

Conclusions: We have identified two novel ABCA4 mutations, c.655A>T and c.5312+3A>T. When present as a compound heterozygous state, the mutations cause a phenotype of retinal dystrophy that initially manifests as Stargardt disease and slowly progresses to a severe cone-rod dystrophy. These results expand the wide range of clinical manifestations of ABCA4 mutations.

Show MeSH
Related in: MedlinePlus