The benign concentric annular macular dystrophy locus maps to 6p12.3-q16.

PURPOSE: 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.

A peculiar autosomal dominant macular dystrophy caused by an asparagine deletion at codon 169 in the peripherin/RDS gene.

OBJECTIVE: To describe the clinical and genetic findings in a family with a peculiar autosomal dominant macular dystrophy with peripheral deposits. METHODS: All family members underwent an ophthalmic examination, and their genomic DNA was screened for mutations in the human retinal degeneration slow (peripherin/RDS) and rhodopsin genes. In selected cases, fluorescein angiography and electrophysiologic testing were performed. RESULTS: The age at onset of the disease was between the third and fourth decades of life, starting with mild visual acuity loss and periods of metamorphopsia. Clinical signs included subretinal yellowish macular deposits evolving into geographic atrophy and retinal hypopigmentation and hyperpigmentation. Electroretinography demonstrated rod dysfunction, and electro-oculograms were mildly to severely disturbed. All affected members were found to carry a 3-base pair deletion affecting codon 169 of the peripherin/RDS gene. This mutation resulted in an asparagine (Asn) deletion in the peripherin/RDS protein and was not found in 155 control individuals. CONCLUSION: A deletion of Asn169 in the peripherin/RDS protein causes a peculiar form of autosomal dominant macular dystrophy in a large family from the Netherlands. CLINICAL RELEVANCE: Characterizing the phenotype and genotype in this family may, in the long term, result in a better understanding of the precise mechanism underlying this retinal degeneration.

Genetic heterogeneity of butterfly-shaped pigment dystrophy of the fovea.

PURPOSE: Butterfly-shaped macular dystrophy (BSMD) has so far only been associated with mutations in the peripherin/RDS gene. The initial aim of our study was to investigate the peripherin/RDS gene as the causative gene in a family with BSMD. Subsequently the putative involvement of the ROM-1 gene, 4 genes expressed in cone photoreceptors, all known non-syndromic macular, retinal pigment epithelium and choroidal dystrophy loci, all known Leber congenital amaurosis loci and all known non-syndromic congenital and stationary retinal disease loci was examined. METHODS: Thirteen members from the original family with autosomal dominant BSMD were examined. The protein coding exons of the peripherin/RDS gene were screened for mutations by sequence analysis. Linkage analysis was performed using markers flanking the peripherin/RDS gene to rule out the presence of a heterozygous deletion. Likewise, involvement of the ROM-1 gene, four cone genes, 41 non-syndromic retinal disease loci and one syndromic retinal disease locus was investigated. RESULTS: Sequence analysis of the peripherin/RDS gene revealed no mutations. In addition, the BSMD phenotype could not be genetically linked to the peripherin/RDS gene, the ROM-1 gene and the four cone genes nor to any of the 42 retinal disease loci. CONCLUSIONS: This study reveals genetic heterogeneity for BSMD by the identification of a BSMD family, which is not associated with a mutation in the peripherin/RDS gene nor with any other known non-syndromic retinal disease gene.

Mutations in the calcium-binding motifs of CDH23 and the 35delG mutation in GJB2 cause hearing loss in one family.

We have ascertained a multi-generation family with apparent autosomal recessive non-syndromic childhood hearing loss (DFNB). Failure to demonstrate linkage in a genome-wide scan with 300 polymorphic markers has suggested genetic heterogeneity for the hearing loss in this family. This heterogeneity could be demonstrated by analysis of candidate loci and genes for DFNB. Patients in one branch of the family (branch C) are homozygous for the 35delG mutation in the GJB2 gene (DFNB1). Patients in two other branches (A and B) carry two new mutations in the cadherin 23 ( CDH23) gene (DFNB12). A homozygous CDH23 c.6442G-->A (D2148N) mutation is present in branch A. Patients in branch B are compound heterozygous for this mutation and the c.4021G-->A (D1341N) mutation. The substituted aspartic acid residues are highly conserved and are part of the calcium-binding sites of the extracellular cadherin (EC) domains. Molecular modeling of the mutated EC domains of CDH23 based on the structure of E-cadherin indicates that calcium-binding is impaired. In addition, other aspartic and glutamic acid residue substitutions in the highly conserved calcium-binding sites reported to cause DFNB12 are also likely to result in a decreased affinity for calcium. Since calcium provides rigidity to the elongated structure of cadherin molecules enabling homophilic lateral interaction, these mutations are likely to impair interactions of CDH23 molecules either with CDH23 or with other proteins. DFNB12 is the first human disorder that can be attributed to inherited missense mutations in the highly conserved residues of the extracellular calcium-binding domain of a cadherin.