Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy

Abstract

Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder of the retinal vascular system. Although mutations in three genes (LRP5, FZD4, and NDP) are known to cause FEVR, these account for only a fraction of FEVR cases. The proteins encoded by these FEVR genes form part of a signaling complex that activates the Norrin-beta-catenin signaling pathway. Recently, through a large-scale reverse genetic screen in mice, Junge and colleagues identified an additional member of this signaling complex, Tspan12. Here, we report that mutations in TSPAN12 also cause autosomal-dominant FEVR. We describe seven mutations identified in a cohort of 70 FEVR patients in whom we had already excluded the known FEVR genes. This study provides further evidence for the importance of the Norrin-beta-catenin signaling pathway in the development of the retinal vasculature and also indicates that more FEVR genes remain to be identified.

Figure 1

Clinical Appearance of FEVR Fundus photograph of the right eye of the proband from family 1 (individual III:2 in Figure S1), showing the retinal vessels drawn up in a retinal fold that is obscuring the macula.

Figure 2

FEVR Is Caused by Mutations in TSPAN12 (A) Sequence traces of the seven mutations identified and the corresponding wild-type alleles. (B) Schematic diagram of TSPAN12, showing the locations of the mutations. (C) Schematic diagram of the TSPAN12 protein, showing the location of the mutations within the protein domains. The locations of the transmembrane domains were obtained from Kovalenko et al., 2005. The intramolecular disulfide bonds crucial for the correct folding of large extracellular loop are indicated by red dots. Because we were unable to assess the actual consequences of the two splicing mutations, only predicted protein outcomes are shown.

Figure 3

Protein Sequence Alignment of Human TSPAN12 with Its Orthologs Alignments were calculated with ClustalW. Accession numbers: Human, O95859; Orangutan, Q5R8B5; Mouse, AAH68240; Rat, Q569A2; Cattle, Q29RH7; Horse, XP_001502093; Dog, XP_855095; Opossum, XP_001364876; Chicken, XP_416007; Zebrafinch, XP_002192381; Platypus, XP_001516347; Zebrafish, NP_957446; Seasquirt Tspan,12 XP_002123238. Only 30 amino acid residues surrounding each mutation are shown. Conserved amino acid residues are highlighted. The positions of the missense mutations p.L101H and p.M210R are indicated.