PMC4057250_01
Cosegregation analysis of the identified alleles and schematic representation of EPHA2 wild-type and mutant proteins. A: Pedigree with genotype data for EPHA2, CRYBB3, and CRYBA2 alleles. Individuals affected with congenital cataract are indicated by shaded symbols. Genotyping results for the three alleles identified in the family are shown below each individual tested: 1 = EPHA2; 2 = CRYBB3; 3 = CRYBA2. The pathogenic allele is indicated in bold. The proband is indicated with an arrow; wt, wild-type allele at the variant position. B: Schematic drawing of the EPHA2 protein and C-terminal extension mutant sequences. The EPHA2 domain structure is shown at the top; SP = signal peptide, FN III = fibronectin III type repeats, TM = transmembrane domain, JMR = juxtamembrane region, SAM = sterile alpha motif, PDZ = PDZ-binding motif. C-terminal sequences of EPHA2 wild-type and frameshift mutants are shown at the bottom with the PDZ-motif residues indicated in blue and erroneous amino acids in red.
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Review of the 37 known cataract genes in the proband identified a novel frameshift variant in the ephrin receptor (EPHA2) gene (Figure 1) and two rare variants in the beta-B3 crystallin (CYRBB3) and beta-A2 crystallin (CRYBA2) genes (Figure 2). The novel frameshift mutation in EPHA2 was present in all three affected family members and was not present in eight unaffected family members, including the unaffected mother, brothers, son, and granddaughters of the proband (Figure 1A). The CRYBB3 variant was present in the proband only, and the CRYBA2 variant was seen in the proband, her affected daughter, and an unaffected brother, but not the affected granddaughter (Figure 1A).
Chromatograms of the EPHA2, CRYBB3, and CRYBA2 alleles. The variant position is indicated with a red arrow.
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Review of the 37 known cataract genes in the proband identified a novel frameshift variant in the ephrin receptor (EPHA2) gene (Figure 1) and two rare variants in the beta-B3 crystallin (CYRBB3) and beta-A2 crystallin (CRYBA2) genes (Figure 2).