Novel TSPAN12 mutations in patients with familial exudative vitreoretinopathy and their associated phenotypes

Abstract

Purpose: Mutations in tetraspanin 12 (TSPAN12) have recently been identified as a cause of autosomal dominant familial exudative vitreoretinopathy (FEVR). The purpose of this study was to detect TSPAN12 mutations in Chinese patients with FEVR and to describe the associated phenotypes.

Methods: Sanger sequencing was used to analyze the seven coding exons and their adjacent regions of TSPAN12 in 49 unrelated FEVR patients. Clinical phenotypes of the patients with TSPAN12 mutations were documented.

Results: Three novel heterozygous mutations in TSPAN12 were identified in three patients from unrelated families: c.146C>T (p.Thr49Met), c.313T>C (p.Cys105Arg), and c.601delC (p.Leu201PhefsX14). All three mutations involved highly conserved residues and were not present in 180 normal individuals. Ocular phenotypes included retinal folds, inferotemporal dragging of the optic disc and macula, increased vessels in the equatorial region, and a peripheral avascular zone. A father and his daughter had the same mutation but the father only had mild peripheral fundus changes while his daughter had obvious dragged disc and macular ectopia.

Conclusions: Our results suggest that TSPAN12 mutations are responsible for FEVR. Similar to patients with mutations in NDP, LRP5, or FZD4, the phenotypes associated with TSPAN12 mutations showed great variations between different individuals within a family and between the two eyes in individual patients.

Figure 1

Mutations identified in TSPAN12. A: The patient in the family had c.146C>T mutation. B; The patient in the family had c.313T>C mutation. C: The affected father and daughter had c.601delC mutation. The columns from left to right display the pedigree and the sequence chromatograms for these patients and the normal controls.

Figure 2

Protein alignment of 12 (TSPAN12) orthologs demonstrates conservation in the regions with mutations. The 12 orthologs are from the following 12 species: Homo sapiens (NP_036470), Pan troglodytes (XP_001142304), Mus musculus (NP_766595), Rattus norvegicus (Q569A2), Bos taurus (NP_001039977), Equus caballus (XP_001502093), Canis familiaris (XP_855095), Monodelphis domestica (XP_001364876), Gallus gallus (NP_001007850), Taeniopygia guttata (XP_002192381), Ornithorhynchus anatinus (XP_001516347), and Danio rerio (NP_957446). The regions with the two missense mutations are highly conserved. T49M stands for p.Thr49Met and C105R stands for p.Cys105Arg.

Figure 3

Fundus changes in the patient with the heterozygous c.313T>C mutation in Family B. A and B: These color photos demonstrate a normal right posterior fundus and traction of the retinal vessels and macular degeneration in the left fundus. C and D: Fluorescein angiography of the left eye shows straightening of the vessels with increasing branching (C) and a peripheral avascular zone (D). OD and OS represent the right and left eyes, respectively.

Figure 4

Fundus changes in the proband with the c.601delC mutation in Family C. A: Inferotemporal dragging of the optic disc and macula is present in the right eye. B: Optical coherence tomography scan shows a flatter central macula in the right eye. C: Inferotemporal dragging of the optic disc and macula is present in the left eye. OD and OS represent the right and left eyes, respectively.

Figure 5

Fundus photos of the asymptomatic father with the c.601delC mutation and the unaffected mother without the mutation. A and B: The mother has normal fundi. C-D: Fundus photos of the asymptomatic father shows normal posterior fundi. E and F: The father has increased vessel branching in the equatorial area and a peripheral avascular zone. G and H: Optical coherence tomography scan shows normal macula of the asymptomatic father.

Figure 6

Schematic representation of TSPAN12 and its familial exudative vitreoretinopathy mutations. Missense mutations are shown above the gene and others below the gene. The 12 mutations listed in this figure included the three from our study (letters in bold) and nine from two previous reports [27,28]. The dark shaded parts in exons 1, 2, and 8 represent the untranslated regions. The vertical lines in exons 2 and 8 indicate the positions of translation start and terminate, respectively.