X-linked retinoschisis: novel mutation in the initiation codon of the XLRS1 gene in a large family.

PURPOSE: To describe a novel point mutation in the initiation codon of the XLRS1 gene in a large family and the clinical features of males affected with X-linked juvenile retino-schisis. METHODS: Genealogic investigation and mutation screening of the XLRS1 gene were performed for a 4-generation family consisting of 72 members. Affected males were evaluated clinically between 1986 and 2004 with up to 18 years of follow-up. RESULTS: We identified a novel point mutation (1A>T transversion) in the initiation codon of the XLRS1 gene in affected males resulting in an amino acid substitution of methionine to leucine (Met1Leu), therefore abolishing the translation initiation Met codon. CONCLUSION: Identification of the disease-causing mutation in this family with long-term follow-up allows for earlier and more accurate identification of individuals at risk for this inherited progressive macular degeneration, provides for more accurate genetic counseling, and contributes to our understanding of the pathophysiology of this disorder.

The role of inflammation in the pathogenesis of age-related macular degeneration.

Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is a complex disease to study because of the potential role of demographic, environmental, and other systemic risk factors, such as age, sex, race, light exposure, diet, smoking, and underlying cardiovascular disease which may contribute to the pathogenesis of this disease. Recently, single nucleotide polymorphisms, DNA sequence variations found within the complement Factor H gene, have been found to be strongly associated with the development of AMD in Caucasians. One single nucleotide polymorphism, Tyr402His, was associated with approximately 50% of AMD cases. We review recent developments in the molecular biology of AMD, including single nucleotide polymorphisms within the Factor H gene, which may predispose individuals to the susceptibility of AMD as well as single nucleotide polymorphisms that may confer a protective effect. Taken together these findings help to provide new insights into the central issues surrounding the pathogenesis of AMD.

X-linked retinoschisis: a clinical and molecular genetic review.

X-linked retinoschisis is a leading cause of macular degeneration in male children. It is characterized by a high degree of clinical variability. Clinical features include a stellate foveal retinoschisis, with or without peripheral retinoschisis. The schisis occurs within the inner retina, primarily at the level of the nerve fiber layer. The disease-causing gene, X-linked retinoschisis 1, has recently been identified, and is expressed in photoreceptor and bipolar cells. This gene codes for retinoschisin, a secreted protein containing a discoidin domain which may be involved in cellular adhesion or cell-cell interactions. The identification of this gene allows for improved diagnosis and contributes to the understanding of this condition. Visual prognosis is variable, as X-linked retinoschisis exhibits a high degree of phenotypic variability. Although there is no treatment to halt the progressive maculopathy, clinical management is directed toward treatment of amblyopia and surgical correction of certain complications. X-linked retinoschisis is an important condition to study, both to improve the clinical management of this disorder, and to better understand retinal function and development. Herein, we review the clinical, histopathologic, and molecular genetic and treatment options of X-linked retinoschisis.

Autosomal dominant Stargardt-like macular dystrophy: identification of a new family with a mutation in the ELOVL4 gene.

PURPOSE: To describe the clinical features and identify the mutation responsible for an autosomal dominant macular degeneration occurring in a four-generation family. METHODS: Family members underwent clinical examination and genealogical characterization. Mutation screening of the ELOVL4 gene was performed. RESULTS: Patients reported visual loss occurring at a mean age of 20 years. Fundus examination revealed varying degrees of central macular atrophy with or without flecks in all affected individuals. DNA sequence analysis showed a 5-bp deletion in exon 6 of the ELOVL4 gene, confirming the diagnosis of autosomal dominant Stargardt-like macular dystrophy. Genealogical analysis showed that this family represents a new affected branch of a previously described 12-generation family (31 branches) with this disorder. CONCLUSIONS: We characterized a new branch of a family with autosomal dominant Stargardt-like macular dystrophy. Identification of the disease-causing gene allows for improved genetic counseling of affected individuals.

X-linked retinoschisis: report of a family with a rare deletion in the XLRS1 gene.

PURPOSE: To describe the clinical features and identify the disease causing mutation in a family with X-linked retinoschisis. DESIGN: Cohort study. METHODS: Genealogical investigation and mutation screening of the XLRS1 gene were performed in a four generation family of Icelandic ancestry. Three affected family members were evaluated clinically over a 29-year period. RESULTS: A rarely reported, four base pair deletion (375- 378 del AGAT) in exon 5 of the XLRS1 gene was found in all affected males. A high degree of intrafamilial variability was observed in the progression of the disorder over 29 years. CONCLUSIONS: Identification of the disease causing mutation in this family allows for the diagnosis of individuals at risk for this inherited macular degeneration. Furthermore, the long-term follow-up of subjects with identical mutations helps to better characterize the highly variable clinical course of this disorder.

Clinical variability of Stickler syndrome: role of exon 2 of the collagen COL2A1 gene.

Stickler syndrome (progressive arthro-ophthalmopathy) is a genetically heterogeneous disorder resulting from mutations in at least three collagen genes. The most common disease-causing gene is COL2A1, a 54-exon-containing gene coding for type II collagen. At least 17 different mutations causing Stickler syndrome have been reported in this gene. Phenotypically, it is also a variably expressed disorder in which most patients present with a wide range of eye and extraocular manifestations including auditory, skeletal, and orofacial manifestations. Some patients, however, present without clinically apparent systemic findings. This observation has led to difficulty distinguishing this Stickler phenotype from other hereditary vitreoretinal degenerations, such as Wagner syndrome and Snowflake vitreoretinal degeneration. In this regard, review of the literature indicates type II collagen exists in two forms resulting from alternative splicing of exon 2 of the COL2A1 gene. One form, designated as type IIB (short form), is preferentially expressed in adult cartilage tissue. The other form, designated as type IIA (long form), is preferentially expressed in the vitreous body of the eye. Because of this selective tissue expression, mutations in exon 2 of the COL2A1 gene have been hypothesized to produce this Stickler syndrome phenotype with minimal or absent extraocular findings. We review the evidence for families with exon 2 mutations of the collagen COL2A1 gene presenting in a distinct manner from families with mutations in the remaining 53 exons, as well as other hereditary vitreoretinal degenerations without significant systemic manifestations.

Autosomal dominant macular dystrophy in a large Canadian family.

BACKGROUND: We studied a large Canadian family (178 total family members) spanning seven generations with autosomal dominant macular dystrophy. We performed a study to identify the gene mutation responsible for the disease in the family. METHODS: Participating family members were evaluated clinically. Genetic linkage, genotyping, mutation screening and an extensive genealogic investigation were performed. RESULTS: The common clinical findings in affected family members included progressive early- to mid-onset visual loss and extensive areas of central chorioretinal atrophy. Two-point linkage analysis indicated linkage to chromosome 6p. Direct DNA sequencing showed a C/T transition in codon 172 of the retinal degeneration slow (RDS) gene creating an amino acid change to Arg172Trp. Haplotype analysis of affected family members using microsatellite markers distributed around the RDS gene locus revealed that the markers were not conserved when compared to members of British families with the Arg172Trp mutation. Genealogic studies indicated the family immigrated to Canada from Ireland in 1843. INTERPRETATION: A newly identified large family with autosomal dominant macular dystrophy is described. The phenotypic appearance of the fundus is similar to that of previously described patients with an Arg172Trp mutation in the RDS gene. Haplotype analysis of markers spanning the disease locus identified a new founder for this mutation. The identification of the disease-causing gene in this family allows for better genetic counselling for patients with this condition and provides a basis to distinguish clinically similar types of macular dystrophy based on the clinical phenotype.

Identification of a stop codon mutation in exon 2 of the collagen 2A1 gene in a large stickler syndrome family.

PURPOSE: To describe the clinical features and identify the mutation responsible for an autosomal dominant vitreoretinal degeneration occurring in a previously unreported large family. DESIGN: Cohort study. METHODS: Family members were evaluated clinically over a 30-year period. Genealogical investigation, genetic linkage to known vitreoretinal degenerations, and mutation screening of the COL2A1 gene were performed. RESULTS: We identified a single large family (2,384 total family members) with vitreoretinal degeneration spanning 12 generations. We reviewed the clinical records of 165 family members (95 affected and 70 unaffected). The common clinical findings in affected individuals included early-onset posterior perivascular retinal degeneration, vitreous degeneration, and retinal detachment. The incidence of retinal detachment was 57% (95/165) and the mean age of onset was 15.2 years. Orofacial, skeletal, and auditory abnormalities were seen in 0%, 5%, and 7.5%, respectively, in a subset of 28 affected subjects. Linkage to the collagen COL2A1 locus was demonstrated and a cytosine to adenosine transition identified within exon 2, leading to the creation of a stop codon at position 86 (Cys86Stop). CONCLUSIONS: Identification of the mutation in this family enables diagnosis of individuals at risk for potentially blinding complications in this condition at an early age. Given the variability of the Stickler phenotype, mutation detection allows for more comprehensive genetic counseling and directs clinical monitoring to family members inheriting the disease gene.