LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma

• Published in: European journal of human genetics : EJHG 2010-07, Vol.18 (7), p.761-767
• Main Authors: Désir, Julie, Sznajer, Yves, Depasse, Fanny, Roulez, Françoise, Schrooyen, Marc, Meire, Françoise, Abramowicz, Marc
• Format: Article
• Language: English
• Subjects: 631/208/737; 692/699/1670/122; 692/700/1720; Base Sequence; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Birth; Body height; Child; Child, Preschool; Children; Cytogenetics; Dislocation; DNA Mutational Analysis; Exon skipping; Extracellular matrix; Eye Abnormalities - complications; Eye Abnormalities - genetics; Families & family life; Female; Fibrillin; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene mapping; General aspects. Genetic counseling; Genes, Recessive - genetics; Genetic Linkage; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Glaucoma; Glaucoma - complications; Glaucoma - genetics; Growth factors; Human Genetics; Humans; Infant; Laboratories; Latent TGF-beta Binding Proteins - genetics; Latent TGF-beta Binding Proteins - metabolism; Lens diseases; Ltbp2 gene; Male; Marfan syndrome; Marfan's syndrome; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; mRNA turnover; Mutation; Mutation - genetics; Myopia; Nonsense-mediated mRNA decay; Ophthalmology; Palate; Pedigree; Phenotypes; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Syndrome; Vision
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2010.11

The latent TGF β -binding proteins (LTBPs) and fibrillins are a superfamily of large, multidomain proteins with structural and TGF β -signalling roles in the extracellular matrix. Their importance is underscored by fibrillin-1 mutations responsible for Marfan syndrome, but their respective roles are still incompletely understood. We report here on two families where children from healthy, consanguineous parents, presented with megalocornea and impaired vision associated with small, round, dislocated lenses (microspherophakia and ectopia lentis) and myopia, as well as a high-arched palate, and, in older children, tall stature with an abnormally large arm span over body height ratio, that is, associated features of Marfan syndrome. Glaucoma was not present at birth, but was diagnosed in older children. Whole genome homozygosity mapping followed by candidate gene analysis identified homozygous truncating mutations of LTBP2 gene in patients from both families. Fibroblast mRNA analysis was consistent with nonsense-mediated mRNA decay, with no evidence of mutated exon skipping. We conclude that biallelic null LTBP2 mutations cause the ocular phenotype in both families and could lead to Marfan-like features in older children. We suggest that intraocular pressures should be followed-up in young children with an ocular phenotype consisting of megalocornea, spherophakia and/or lens dislocation, and recommend LTBP2 gene analysis in these patients.