Homozygous null mutations in the ABCA4 gene in two families with autosomal recessive retinal dystrophy.
OBJECTIVE
To identify the genes causing autosomal recessive retinal dystrophy in Indian families and to characterize the associated phenotypes.


METHODS
Experimental and observational.


METHODS
Families with autosomal recessive nonsyndromic retinal dystrophies were recruited. Complete ophthalmic evaluation, including visual acuity, visual fields, fundus examinations, and electroretinography, was performed on all members. Genotyping of 14 families for two or more microsatellite markers flanking each of 21 different genes causing retinal dystrophy was done by standard methods to screen for the presence of homozygosity by descent. Mutational screening of the ABCA4 gene was carried out on 18 members (five affected) of two families by amplification and direct automated sequencing of exons and flanking sequences. Sequence alterations identified were tested for cosegregation with disease in the families and for presence in 100 unrelated normal controls.


RESULTS
Two of 14 families showed homozygosity shared by affected individuals for markers flanking the ABCA4 locus. A homozygous nonsense mutation in the ABCA4 gene of Arg2030Stop was found in one family and a homozygous single base deletion leading to frameshift at Arg409 was found in the second family. Both of these mutations were found to cosegregate with disease. Five affected individuals from the two families had early-onset visual loss, diminished rod and cone electroretinographic responses, and widespread atrophy of the retinal pigment epithelium.


CONCLUSIONS
Homozygous null mutations in ABCA4 produced a severe widespread retinal degeneration that showed marked central retinal involvement.
Kallam Anji Reddy Molecular Genetics Laboratory, L.V. Prasad Eye Institute, L.V. Prasad Marg, Banjara Hills, Hyderabad 500-034, India.
Hardeep Pal
HP
Singh
Subhadra
S
Jalali
J Fielding
JF
Hejtmancik
Chitra
C
Kannabiran
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D014786:Vision Disorders / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D014792:Visual Acuity; D014794:Visual Fields
C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D018389:Codon, Nonsense