The benign concentric annular macular dystrophy locus maps to 6p12.3-q16.
OBJECTIVE
To describe the clinical findings and to identify the genetic locus in a Dutch family with autosomal dominant benign concentric annular macular dystrophy (BCAMD).


METHODS
All family members underwent ophthalmic examination. Linkage analysis of candidate retinal dystrophy loci and a whole genome scan were performed. Five candidate genes from the linked locus were analyzed for mutations by direct sequencing.


RESULTS
The BCAMD phenotype is initially characterized by parafoveal hypopigmentation and good visual acuity, but progresses to a retinitis pigmentosa-like phenotype. Linkage analysis established complete segregation of the BCAMD phenotype (maximum multipoint LOD score, 3.8) with DNA markers at chromosome 6, region p12.3-q16. Recombination events defined a critical interval spanning 30.7 cM at the long arm of chromosome 6 between markers D6S269 and D6S300. This interval encompasses several retinal dystrophy loci, including the ELOVL4 gene, mutated in autosomal dominant Stargardt disease, and the RIM1 gene, mutated in autosomal dominant cone-rod dystrophy, as well as the retinally expressed GABRR1 and -2 genes. Mutation screening of these four genes revealed no mutations. Sequence analysis of the interphotoreceptor matrix proteoglycan 1 gene IMPG1, also residing in the BCAMD locus, revealed a single base-pair change (T-->C) of nucleotide 1866 in exon 13, resulting in a Leu579Pro amino acid substitution. This mutation was absent in 190 control individuals.


CONCLUSIONS
Significant linkage was found for the BCAMD defect with chromosomal 6, region p12.3-q16. A Leu579Pro mutation in the IMPG1 gene may play a causal role.
van Lith-Verhoeven
Janneke J C
JJ
Department of Ophthalmology, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Hoyng
Carel B
CB
van den Helm
Bellinda
B
Deutman
August F
AF
Brink
Hendrik M A
HM
Kemperman
Martijn H
MH
de Jong
Wendy H M
WH
Kremer
Hannie
H
Cremers
Frans P M
FP
D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D005260:Female; D005500:Follow-Up Studies; D008040:Genetic Linkage; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation; D011509:Proteoglycans; D014792:Visual Acuity
D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D006023:Glycoproteins; C486428:IMPG1 protein, human; D011509:Proteoglycans