A Nonsense Mutation in CRYBB1 Associated with Autosomal Dominant Cataract Linked to Human Chromosome 22q Donna S. Mackay, Olivera B. Boskovska, Harry.

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A Nonsense Mutation in CRYBB1 Associated with Autosomal Dominant Cataract Linked to Human Chromosome 22q Donna S. Mackay, Olivera B. Boskovska, Harry L.S. Knopf, Kirsten J. Lampi, Alan Shiels The American Journal of Human Genetics Volume 71, Issue 5, Pages 1216-1221 (November 2002) DOI: 10.1086/344212 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree and haplotype analysis of family ADC4, showing segregation of four microsatellite markers (in descending order from the centromere) on chromosome 22. Squares and circles symbolize male and female individuals, respectively; blackened symbols denote affected status. The American Journal of Human Genetics 2002 71, 1216-1221DOI: (10.1086/344212) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 Idiogram of chromosome 22, showing the integrated genetic and physical order of microsatellite markers across the CRYB gene cluster. Physical distances between markers and genes are shown. Two-point Z values for linkage between the cataract and markers are indicated. An asterisk denotes the intragenic marker CRYBB2-CA. Arrows show the direction of gene transcription. The American Journal of Human Genetics 2002 71, 1216-1221DOI: (10.1086/344212) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutation analysis of CRYBB1. A, Sequence chromatograms of wild-type allele, showing translation of glycine (GGA) at codon 220. B, Sequence chromatograms of mutant allele, showing a G→T transversion that changed glycine 220 to a stop codon (TGA). C, Mutant allele–specific primer extension analysis. Exon 6 was amplified in the presence of three PCR primers (as indicated by arrows): a sense anchor primer located in intron 5, an antisense primer located in the 3′ UTR, and a nested antisense primer specific for the G→T mutation in codon 220. Unaffected individuals have only the wild-type G allele (292 bp), whereas, affected individuals also have the mutant T allele (189 bp). D, Amino acid alignment of the fourth Greek-key motif of βB1-crystallin (codons 193–234) with that of βB2-crystallin (codons 151–192). Colons indicate identical amino acids. “X” indicates premature-chain-termination mutations in human βB1 (G220X) and βB2 (Q155X). The locations of a missense substitution (V187E) and an in-frame deletion (hyphens) in βB2 from the Aey2 (Graw et al. 2001) and Philly (Chambers and Russell 1991) mouse mutants, respectively, are also indicated. The American Journal of Human Genetics 2002 71, 1216-1221DOI: (10.1086/344212) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 4 Expression of recombinant human βB1-crystallin in E. coli. A and B, SDS-PAGE (A) and immunoblot (B) analyses of wild-type βB1 and G220X-βB1 in the soluble (S) and insoluble pellet (P) fractions, before (−) and after (+) induction with IPTG. Lane M shows molecular mass-markers; lanes 1, 3, 5, and 7 show uninduced cell lysates, and lanes 2, 4, 6, and 8 show induced cell lysates; lanes 1, 2, 5, and 6 show soluble proteins, and lanes 3, 4, 7, and 8 show insoluble proteins. C, MS/MS spectrum, identifying the C-terminal peptide (HWNEW) derived from the G220X-βB1 mutant in band b excised from the gel (lane 8) shown in panel A. The inset shows masses of the expected fragment ions; intact N-terminal ions (b-ions) and C-terminal ions (y-ions) that were found in the spectrum are underlined. The American Journal of Human Genetics 2002 71, 1216-1221DOI: (10.1086/344212) Copyright © 2002 The American Society of Human Genetics Terms and Conditions