title: A homozygous mutation in LTBP2 causes isolated microspherophakia.
abstract: Microspherophakia is an autosomal-recessive congenital disorder characterized by small spherical lens. It may be isolated or occur as part of a hereditary systemic disorder, such as Marfan syndrome, autosomal dominant and recessive forms of Weill-Marchesani syndrome, autosomal dominant glaucoma-lens ectopia-microspherophakia-stiffness-shortness syndrome, autosomal dominant microspherophakia with hernia, and microspherophakia-metaphyseal dysplasia. The purpose of this study was to map and identify the gene for isolated microspherophakia in two consanguineous Indian families. Using a whole-genome linkage scan in one family, we identified a likely locus for microspherophakia (MSP1) on chromosome 14q24.1-q32.12 between markers D14S588 and D14S1050 in a physical distance of 22.76 Mb. The maximum multi-point lod score was 2.91 between markers D14S1020 and D14S606. The MSP1 candidate region harbors 110 reference genes. DNA sequence analysis of one of the genes, LTBP2, detected a homozygous duplication (insertion) mutation, c.5446dupC, in the last exon (exon 36) in affected family members. This homozygous mutation is predicted to elongate the LTBP2 protein by replacing the last 6 amino acids with 27 novel amino acids. Microspherophakia in the second family did not map to this locus, suggesting genetic heterogeneity. The present study suggests a role for LTBP2 in the structural stability of ciliary zonules, and growth and development of lens.
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, 560012, India. karun@mrdg.iisc.ernet.in
authors.forename: Arun
authors.initials: A
authors.lastname: Kumar
authors.forename: Maheswara R
authors.initials: MR
authors.lastname: Duvvari
authors.forename: Venkatesh C
authors.initials: VC
authors.lastname: Prabhakaran
authors.forename: Jyoti S
authors.initials: JS
authors.lastname: Shetty
authors.forename: Gowri J
authors.initials: GJ
authors.lastname: Murthy
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics*; D005192:Family Health; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D007194:India; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics*; D007908:Lens, Crystalline / Q000002:abnormalities*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree
chemical_list: C509035:LTBP2 protein, human; D053779:Latent TGF-beta Binding Proteins