PMC3724954_01
Pedigrees of three Chinese families with hereditary vitreous amyloidosis. The filled symbols indicate patients with vitreous amyloidosis. Penetrance of disease varied in Family A, Family B, and Family C. The probands are marked with arrows. The samples with a slash indicate deceased individuals.
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Eleven of 30 members in this family (including one deceased patient, I:1) experienced vision loss in their 30s (Figure 1A). Eight of 83 members of Family B had ophthalmologic features of FAP (Figure 1B).
Ophthalmologic examinations of the left eye of the proband (III:20) from Family A. Slit-lamp photograph (A) and dilated fundus examination (B) show the floccular turbid of the vitreous body. B-mode ultrasonography shows the high echo in the vitreous body (C). Histochemical examination of vitrectomy specimen stained with Congo red shows amyloid deposits (in red; D).
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Amyloidosis and high echoes were identified with the slit-lamp photograph test and B-mode ultrasonography (Figure 2), respectively. Pathological examination of Congo red staining showed amyloid deposition in the vitreous body of all probands (Figure 2).
Analysis of the pathogenic mutation p.G83R of the transthyretin (TTR) protein in vertebrates. A: The sequencing electropherogram shows the mutated region in a normal control (III:23) and a patient (III:21) in Family B. B: Evolutionary analysis of position 83 in the TTR protein is shown. Protein sequences of Homo sapiens (CAG33189), Pan troglodytes (NP_001009137), Mus musculus (AAH24702), Rattus norvegicus (NP_036813), Bos taurus (NP_776392), Ovis aries (NP_001009800), Sus scrofa (NP_999377), Gallus gallus (NP_990666), Xenopus laevis (NP_001081348), and Danio rerio (AAI64894) were retrieved from GenBank.
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We amplified and sequenced the most common candidate gene, the TTR gene, and detected only a rare missense heterozygous mutation c.307G>C (p.G83R) in exon 3 of the probands of the three families (Figure 3A). Conservation analysis of ten vertebrate species indicated this rare mutation changed a highly conserved glycine to arginine in position 83 of the TTR protein (Figure 3B).
Comparison of homology modeling predicted transthyretin protein with and without mutant p.G83R. The side chain of the mutant was changed by p.G83R.
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As shown in Figure 4, the predicted three-dimensional structure of the TTR protein was changed by p.G83R.