J. Bronwyn Bateman

Multiple and Additive Functions of ALDH3A1 and ALDH1A1 CATARACT PHENOTYPE AND OCULAR OXIDATIVE DAMAGE IN Aldh3a1(-/-)/Aldh1a1(-/-) KNOCK-OUT MICE

ALDH3A1 (aldehyde dehydrogenase 3A1) is abundant in the mouse cornea but undetectable in the lens, and ALDH1A1 is present at lower (catalytic) levels in the cornea and lens. To test the hypothesis that ALDH3A1 and ALDH1A1 protect the anterior segment of the eye against environmentally induced oxidative damage, Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out and Aldh1a1(-/-) and Aldh3a1(-/-) single knock-out mice were evaluated for biochemical changes and cataract formation (lens opacification). The Aldh1a1/Aldh3a1- and Aldh3a1-null mice develop cataracts in the anterior and posterior subcapsular regions as well as punctate opacities in the cortex by 1 month of age. The Aldh1a1-null mice also develop cataracts later in life (6–9 months of age). One- to three-month-old Aldh-null mice exposed to UVB exhibited accelerated anterior lens subcapsular opacification, which was more pronounced in Aldh3a1(-/-) and Aldh3a1(-/-)/Aldh1a1(-/-) mice compared with Aldh1a1(-/-) and wild type animals. Cataract formation was associated with decreased proteasomal activity, increased protein oxidation, increased GSH levels, and increased levels of 4-hydroxy-2-nonenal- and malondialdehyde-protein adducts. In conclusion, these findings support the hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via nonenzymatic (light filtering) and enzymatic (detoxification) functions.

Ligneous conjunctivitis: an autosomal recessive disorder.

Two siblings, a boy and a girl, developed a chronic, bilateral conjunctivitis with large recurrent pseudomembranes. The diagnosis of ligneous conjunctivitis was made by excisional biopsies in both. The family was referred for genetic counseling after the second child developed the disorder. On the basis of this family and previous reports, we believe that ligneous conjunctivitis is a genetic disorder inherited in an autosomal recessive pattern and that genetic counseling should be offered to the parents of affected children.

Clinical variability of autosomal dominant cataract, microcornea and corneal opacity and novel mutation in the alpha A crystallin gene (CRYAA).

We studied 28 individuals from a four‐generation Chilean family (ADC54) including 13 affected individuals with cataracts, microcornea and/or corneal opacity. All individuals underwent a complete ophthalmologic exam. We screened with a panel of polymorphic DNA markers for known loci that cause autosomal dominant cataracts, if mutated, and refined the locus using the ABI Prism Linkage Mapping Set Version 2.5, and calculated two‐point lod scores. Novel PCR primers were designed for the three coding exons, including intron–exon borders, of the candidate gene alpha A crystallin (CRYAA). Clinically, affected individuals had diverse and novel cataracts with variable morphology (anterior polar, cortical, embryonal, fan‐shaped, anterior subcapsular). Microcornea and corneal opacity was evident in some. Marker D21S171 gave a lod score of 4.89 (θm = θf = 0). CRYAA had a G414A transition that segregated with the disease and resulted in an amino acid alteration (R116H). The phenotypic variability within this family was significant with novel features of the cataracts and a corneal opacity. With the exception of iris coloboma, the clinical features in all six previously reported families with mutations in the CRYAA gene were found in this family. We identified a novel G414A transition in exon 3 of CRYAA that co‐segregated with an autosomal dominant phenotype. The resulting amino acid change R116H is in a highly conserved region and represents a change in charge. The genotype–phenotype correlation of this previously unreported mutation provides evidence that other factors, genetic and/or environmental, may influence the development of cataract as a result of this alteration.

Eye Disease and Care in Latin America and the Caribbean

In the last decade, health indicators in Latin America and the Caribbean reflect advances. The per capita public expenditure on health care has increased in many countries. Despite these improvements, it is estimated that for every million population in Latin America and the Caribbean, 5,000 are blind and 20,000 are visually impaired; at least 66% of the blindness is attributable to treatable conditions such as cataract. The cataract surgery rate in the region remains low as compared to the industrialized countries, although it is higher than many other regions of the world. The availability of eye care services varies from country to country within the region, and the number of ophthalmologists per million population in the richest countries may be nine times more than in the poorest. Access, defined as the distance between the consumer and the services, is problematic in countries with isolated areas in the rainforest or high mountains, poor road systems, or lack of public transportation. Affordability is an important issue that limits utilization of services by the poorest segments of the population in nearly all countries in Latin America and the Caribbean.

Gene Conversion Mutation in Crystallin, β-B2 (CRYBB2) in a Chilean Family with Autosomal Dominant Cataract

PURPOSE To map and identify the mutated gene for autosomal dominant cataract (ADC) in a large Chilean family (ADC53). DESIGN Experimental study. PARTICIPANTS Large Chilean family with ADCs. METHODS Linkage analyses using genome-wide polymorphic DNA markers were performed on a family with variable expression of cataracts to map the mutated gene to a chromosome; 2-point lod scores were calculated. Candidate genes in the region of the maximum lod score were sequenced. We compared haplotypes (alleles at closely linked markers) in families with previously reported mutations of the crystallin, beta-B2 gene (CRYBB2). MAIN OUTCOME MEASURES Identification of the causative mutation in the ADC53 family. RESULTS The ADC locus mapped to chromosome 22 in the region of a cluster of lens beta crystallin genes (CRYBB3, CRYBB2, CRYBB1, and CRYBA4 and the pseudogene CRYBB2P1). We sequenced CRYBB1 and CRYBB2 and found a previously reported mutation and a variant in exon 6 of CRYBB2 that cosegregate with the disease; these changes in CRYBB2 are in the reference (normal) sequence of an adjacent gene CRYBB2P1, a pseudogene. The haplotypes in the ADC53 Chilean family were different from the 2 previously reported families with the mutation. CONCLUSIONS The cataracts in the ADC53 Chilean family are caused by a mutation in the CRYBB2 gene; as the 2 variations in CRYBB2 are identical to the reference sequence of pseudogene CRYBB2P1, which has over 97% homology to CRYBB2, a gene conversion probably has occurred. Based on haplotype analyses, the mutation and variant are likely to be caused by independent gene conversions in our family and the previously reported families.

Assignment of the αB-crystallin gene to human chromosome 11

Using a human alpha B-crystallin genomic probe and human-mouse somatic cell hybrids, the human alpha B-gene was assigned to chromosome 11 and further corroborated by in situ hybridization to normal metaphase chromosomes. This assignment confirmed and regionally mapped the locus to q22.3-23.1.

Assignment of the gene (RLBP1) for cellular retinaldehyde-binding protein (CRALBP) to human chromosome 15q26 and mouse chromosome 7

Cellular retinaldehyde-binding protein (CRALBP) has properties that suggest that it is involved in the visual process and, therefore, potentially with retinal diseases. A human cDNA probe has been used to map this gene to human chromosome 15q26 (somatic cell hybrids and in situ hybridization) and to mouse chromosome 7 by somatic cell hybrids.

Colobomatous macrophthalmia with microcornea

The ocular malformation of microcornea, uveal coloboma, high myopia, posterior staphyloma, and macrophthalmia was studied in a family. Clinical characteristics and ocular parameters, including refractive error and axial length, are summarized. The pedigree is consistent with autosomal dominant inheritance of the disorder; expressivity is variable. This unique malformation is differentiated from other well-recognized syndromes of colobomatous microphthalmia.

Menkes disease : New ocular and electroretinographic findings

OBJECTIVE The authors describe new ocular and electroretinographic (ERG) features in Menkes disease. DESIGN The study design is a case report. PARTICIPANTS The authors studied two patients with Menkes disease. INTERVENTION The authors performed complete ophthalmologic and ERG evaluations in both patients. MAIN OUTCOME MEASURES The parameters used were slit-lamp biomicroscopy and ERG recordings. RESULTS Aberrant lashes and anterior stromal hypoplasia of the iris are new findings, and profound delays in b-wave implicit time in well-developed photopic responses may be added as new ERG features. CONCLUSIONS Patients with Menkes disease may have aberrant lashes, anterior stromal hypoplasia, and retinal degeneration.

Endogenous Endophthalmitis Caused by Streptococcus mitis

PURPOSE To report endogenous endophthalmitis caused by Streptococcus mitis. METHODS A 3-year-old girl was hospitalized for possible retinoblastoma after she suddenly developed a red and sensitive left eye. After administration of anesthesia, we examined the patient and obtained samples of aqueous, vitreous, and blood for culture. RESULTS Blood and vitreous cultures grew S mitis. Intravenous and intravitreal injections of antibiotics were used to treat the infection. CONCLUSIONS Streptococcus mitis should be considered a cause of endogenous endophthalmitis.