Genomewide Homozygosity Mapping and Molecular Analysis of a Candidate Gene Located on 22q13 (Fibulin-1) in a Previously Undescribed Vitreoretinal Dystrophy

Abstract

Objectives:To localize the gene that causes an autosomal recessively inherited vitreoretinal dystrophy that has not been described, to our knowledge, and to analyze a candidate gene mapped to 22q13 (fibulin-1 [FBLN1]).Methods: Homozygosity mapping with 500 microsatellite markers spread over the whole genome (mean distance, 7.2 centimorgans [cM]) and mutation analysis of the complete coding region of FBLN1.Results: Homozygosity for all analyzed markers was found in the 4 affected siblings in a region on chromosome 22 encompassing 12 cM from D22S444 (centro-meric) to D22S1170 (telomeric). Lod scores were between 0.017 and 2.36 (theta=0). A mutation analysis of the complete coding region of FBLN1, which encodes interacting extracellular matrix proteins, revealed 4 previously undescribed single nucleotide polymorphisms.Conclusions: A genomewide homozygosity mapping analysis supported the hypothesis that the gene responsible for a unique vitreoretinal dystrophy is located on chromosome 22q13. No obviously pathogenic mutation was found in the candidate gene, FBLN1.

Anti‐Ro/SSA autoantibody‐mediated regulation of extracellular matrix fibulins in human epithelial cells of the salivary gland

“…The importance of fibulins in development and disease has been demonstrated by gene-targeting experiments in animal models and the identification of spontaneous mutations in humans (35)(36)(37). The involvement of fibulins has been demonstrated in inherited eye disorders (38,39), and homozygosity for a missense mutation in fibulin 5 is also associated with a severe form of cutis laxa and a scarcity of elastic fibres (40). Fibulin dysregulation has also been correlated with cancer (41)(42)(43).…”

Clinical features of the congenital vitreoretinopathies

“…The condition was linked to chromosome 22q13. 46 Figure 5 Snowflake vitreoretinal degeneration (SVD). A fundus photograph of a patient in the original Snowflake family first published by Hirose et al and re-assessed by Lee et al 40,41 Note the flat dysmorphic optic nerve head, sheathing of vessels on the optic nerve head, fibrillar degeneration of the vitreous, and peripheral chorioretinal atrophy.…”

Role of tyrosine-sulfated proteins in retinal structure and function

“…Fibulin 5 and 6 have been associated with macular dystrophy (Schultz et al 2003; Stone et al 2004). Fibulin 1 has been implicated in recessive vitreoretinal dystrophy (Weigell-weber et al 2003). Genome-wide homozygosity mapping with microsatellite markers mapped the candidate gene to 22q13, where fibulin 1 is located (Weigell-weber et al 2003).…”

“…Fibulin 1 has been implicated in recessive vitreoretinal dystrophy (Weigell-weber et al 2003). Genome-wide homozygosity mapping with microsatellite markers mapped the candidate gene to 22q13, where fibulin 1 is located (Weigell-weber et al 2003). Therefore, fibulin 2 may also be involved in ocular disease.…”