Gail Billingsley, Sathiyavedu T. Santhiya, Andrew D

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CRYBA4, a Novel Human Cataract Gene, Is Also Involved in Microphthalmia Gail Billingsley, Sathiyavedu T. Santhiya, Andrew D. Paterson, Koji Ogata, Shoshana Wodak, S. Mohsen Hosseini, Shyam Manohar Manisastry, Perumalsamy Vijayalakshmi, Pudhiya Mundyat Gopinath, Jochen Graw, Elise Héon The American Journal of Human Genetics Volume 79, Issue 4, Pages 702-709 (October 2006) DOI: 10.1086/507712 Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 1 Family C132 pedigree, with haplotypes. Affected individuals (blackened symbols) with a haplotype were clinically examined. “Unaffected” individuals (unblackened symbols) were not examined. Individuals III:18 and IV:13 defined the upper boundary of the disease interval and excluded CRYBB2 (exons 1–3) and CRYBB3 as candidate genes. A lower boundary for the disease interval was not identified. The affected haplotype is depicted in red. The American Journal of Human Genetics 2006 79, 702-709DOI: (10.1086/507712) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 2 Comparative sequence analysis of CRYBA4. Red, pathogenic amino acid change; yellow, change of uncertain pathogenicity. The American Journal of Human Genetics 2006 79, 702-709DOI: (10.1086/507712) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 3 Homology modeling of CRYBA4. A, Modeled structure of CRYBA4. Depicted is the N-terminal domain of the predicted atomic structure of CRYBA4, built using the known structure of 1oki_A as template (see text). The protein backbone is drawn using a solid ribbon model. α-Helix, β-strand, and turn structures are colored in red, cyan, and light green, respectively. Val36, Leu69, and Phe94 residues are shown in full atomic detail. B, Environment of the Phe94 and Ser94 side chains in the modeled CRYBA4 three-dimensional structure. The side chains of Phe94 and Ser94 are colored in blue and orange, respectively. Residues whose atoms are <6.0 Å from the side-chain atoms of Phe94 are shown. The ∼100-Å3 cavity formed by replacing the bulky Phe 94 with Ser is outlined by the mesh colored in cyan. This cavity is lined by the side chains of hydrophobic residues surrounding Ser94. The cavity volume was computed using the ProShape software, with a probe radius of 0.2 Å, which approximates the cavity delimited by the molecular surface of the surrounding residues. C, Portion of the CRYBA4 structure in the vicinity of residue 69, highlighting the differences in the β-sheet backbone structures of the wild-type (Leu69) and mutant (Pro69) proteins. The backbone nitrogen of Leu69 forms a hydrogen bond with the carbonyl group of Trp54, contributing to the stability of the antiparallel β-sheet structure. This hydrogen bond cannot form in the Pro69 mutant. Its backbone nitrogen cannot act as a hydrogen-bond donor, since it is covalently linked to the proline ring. The American Journal of Human Genetics 2006 79, 702-709DOI: (10.1086/507712) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 4 Sequence logo representation (WebLogo) of the conservation pattern at specific residue positions in CRYBA4. The logo represents the position-specific information content (conservation level), in bits, of the multiple sequence alignments computed using BLAST CRYBA4 sequences. The indicated residue positions follow the numberings of the CRYBA4 sequence. The total height of each column is proportional to the information content (conservation) of the corresponding position, and the height of a letter in a column (representing a given amino acid, using the one-letter code) is proportional to its frequency at that position.33,34 The American Journal of Human Genetics 2006 79, 702-709DOI: (10.1086/507712) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 5 Expression profile of CRYBA4 in eye tissues. Lanes 1–7 represent adult eye tissues: 1, sclera; 2, cornea; 3, iris; 4, ciliary body; 5, lens; 6, choroid; 7, retina. Lanes 8–11 are from newborn eye tissues: 8, cornea; 9, lens; 10, choroids; 11, retina. Lane 12 is RT-minus. Lane 13 is no-template control (no cDNA template in the PCR). M, molecular size marker. A duplex PCR was performed on cDNA obtained from different tissues by use of amplification of GAPDH transcript as control for the quality and quantity of RT-PCR templates. Upper band (A) represents the 640-bp PCR product of amplification with CRYBA4-specific primers, exon 2–6 (amplified only in lens tissues), whereas the lower band (B) is the result of amplification with GAPDH-specific primers. Numbers on the left show fragment size in base pairs. Samples 1–7 and 8–11 were amplified at the same time with the same concentration of GAPDH. PCR products were electrophoresed on 2% agarose gels stained with ethidium bromide. The American Journal of Human Genetics 2006 79, 702-709DOI: (10.1086/507712) Copyright © 2006 The American Society of Human Genetics Terms and Conditions