N965S is a common ABCA4 variant in Stargardt-relatedretinopathies in the Danish population

[摘要] Purpose: The study was conducted to resolve the spectrum of ABCA4mutations in a cohort of unrelated Danish residents with early-onsetmacular dystrophy.Methods: A microarray technique was used to analyze known ABCA4mutations in genomic DNA from a selected group of 161 unrelatedindividuals referred to the national low vision clinic. The clinicalobservation time varied from a single examination to follow-up over 35years.Results: Fifty-nine allegedly disease-associated ABCA4 variants werefound in 197 alleles (61.2%) from 124 (77.0%) patients. Two or threemutations were present in 73 (45.3%) patients, and only one mutation wasfound in 51 (31.7%) patients. The mutation spectrum included 45 missensemutations, five nonsense mutations, two frame shift deletions, and sevensplice site mutations. The relative frequency among the mutations variedconsiderably. Twenty-eight mutations occurred only once among 197alleles, while the five most abundant mutations were encountered in 50%of the mutation-carrying alleles. The rate of mutation detection,assessed as the fraction of individuals carrying at least one ABCA4mutation, varied from 27% to 90% among seven phenotypic groups, and asingle mutation, p.N965S (c.2894A>G) in the first nucleotide-bindingdomain accounted for 16.2% of 197 disease-associated alleles. Themutation causes moderate to serious phenotypes and eventuallyblindness.Conclusions: Our study is the first mutation analysis ofStargardt-related retinopathies in a large cohort of patients from aScandinavian population. The mutation detection rate, performed with anarray-based technique, was comparable to that of other microarray-basedABCA4 studies as well as studies using more laborious techniquesinvolving screening methods followed by sequencing. Four out of five ofthe most prevalent ABCA4 mutations are reported to be frequent in otherWestern European populations as well. However, the prevalence of themost common Danish mutation, N965S, significantly deviates from the onefound in other studies. This underscores that the ABCA4 mutationspectrum within relatively stable populations might be skewed due tofounder effects. The clinical spectrum of patients, who are eitherhomozygous or compound heterozygous for the N965S mutation, indicatesthat this mutation has an early and profound effect on retinalfunction.

[学科分类] 生物化学/生物物理