Molecular Vision 2006; 12:1033-9 <http://www.molvis.org/molvis/v12/a116/> Received 3 July 2006 | Accepted 29 August 2006 | Published 1 September 2006 Hereditary congenital and/or infantile cataracts (CC) exhibit extreme phenotypic variability as to lens opacities, giving rise to vivid designations such as stellate, pulverulent, floriform, pisciform, coralliform, or breadcrumb-like cataract. As regards localization within the lens substance, the most frequent morphological types of CC are confined to the nucleus, the lens sutures, the perinuclear layers (lamellar or zonular cataracts), the cortex, the anterior or posterior polar regions, or combinations of these [1]. Within families, the cataract phenotype often belongs to the same morphological category. “Ant-egg” cataract is an ex- tremely rare phenotype, first described in a five generation family from Rostock, Germany [2,3]. A second family like- wise exerting autosomal dominant transmission was reported from Graz, Austria in 1939 [4]. A third family of Danish ex- traction was presented by Riise in 1967 [5]. In addition an isolated case was published by Jaeger who introduced the name “Ameiseneierkatarakt” [6]. The “ant-egg” phenotype is a lamellar cataract with dense pearl-like or ant-egg-like structures imbedded in the lens, pri- marily confined to the perinuclear layers and to a lesser de- gree in the fetal nucleus, leaving a clear cortical periphery. During and after lens extraction these extremely hard lens in- clusions are liberated from the rest of the fragmented lens material and deposited in the anterior chamber, primarily on the anterior surface of the iris (Figure 1). The mechanism leading to these peculiar formations have been subject to dispute. Riedl [4] held the opinion that the elements which he named “lentoids” were due to an abortive regeneration process originating from epithelial cells liberated during lens extraction. This hypothesis was supported by the observation of the formation of lentoids up to several years after lens extraction. However, unlike the other authors, Riedl did not have the opportunity to observe the cataracts prior to operation. According to the opposed view, the ant-egg-like forma- tions are the result of a degenerative process of the lens fibers surrounding the fetal nucleus [4,6]. In order to further eluci- date the molecular mechanism behind the ant-egg formation we retrieved the Danish family in order to perform linkage and mutation analyses. METHODS Patients: The family (CC00103) was identified from a na- tional register of hereditary eye diseases kept at the National Eye Clinic in Hellerup, Denmark. The pedigree (Figure 2A) was updated through The Danish Civil Registration System ©2006 Molecular Vision The congenital “ant-egg” cataract phenotype is caused by a missense mutation in connexin46 Lars Hansen, 1,2 Wenliang Yao, 3 Hans Eiberg, 2 Mikkel Funding, 4 Ruth Riise, 5 Klaus Wilbrandt Kjaer, 1,2 James Fielding Hejtmancik, 3 Thomas Rosenberg 6 1 The Wilhelm Johannsen Centre for Functional Genome Research, Institute of Medical Biochemistry and Genetics and 2 Institute of Medical Biochemistry and Genetics, Department G, Panum Institute, University of Copenhagen, Copenhagen, Denmark; 3 Section on Ophthalmic Molecular Genetics, National Eye Institute, NIH, Bethesda, MD; 4 Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark; 5 Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway; 6 Gordon Norrie Centre for Genetic Eye Diseases, Kennedy Institute-National Eye Clinic, Hellerup, Denmark Purpose: “Ant-egg” cataract is a rare, distinct variety of congenital/infantile cataract that was reported in a large Danish family in 1967. This cataract phenotype is characterized by ant-egg-like bodies embedded in the lens in a laminar configu- ration and is inherited as an autosomal dominant trait. We retrieved the family and performed linkage analysis to deter- mine the disease locus and identify the mutated gene. Methods: The family (CC00103) was identified in a National Register of Hereditary Eye Diseases and updated based on The Danish Civil Register System. Genome wide linkage analysis and haplotyping using STS marker systems were carried out to achieve a LOD score above 3. The disease-causing candidate gene was sequenced and the mutation was identified and verified by restriction enzyme digestion of genomic DNA from all individuals in family CC00103 and 60 healthy controls. Results: Linkage analysis resulted in a LOD score of 3.91 for marker D13S1275 located close to the known cataract gene GJA3. A novel missense mutation c.32T>C (L11S), was found by sequencing DNA from two affected members. The mutation was present in all affected individuals and was neither found in unaffected family members nor in 60 healthy individuals by restriction enzyme digests. Conclusions: The congenital “ant-egg” cataract phenotype is caused by a L11S mutation in connexin46 (Cx46) located in the signal peptide domain. Further studies are needed to unravel the mechanism leading to the formation of the “ant-eggs”. Correspondence to: Thomas Rosenberg, PhD, Gordon Norrie Centre for Genetic Eye Diseases, Kennedy Institute-National Eye Clinic, 1 Rymarksvej, DK-2900 Hellerup, Denmark; Phone: +45 39452400; FAX: +45 39452420; email: roseeye@visaid.dk 1033