A Mutation in the Variable Repeat Region of the Aggrecan Gene (AGC1) Causes a Form of Spondyloepiphyseal Dysplasia Associated with Severe, Premature.

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A Mutation in the Variable Repeat Region of the Aggrecan Gene (AGC1) Causes a Form of Spondyloepiphyseal Dysplasia Associated with Severe, Premature Osteoarthritis Lindsay Gleghorn, Rajkumar Ramesar, Peter Beighton, Gillian Wallis The American Journal of Human Genetics Volume 77, Issue 3, Pages 484-490 (September 2005) DOI: 10.1086/444401 Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of family with SEDK. Blackened circles and squares represent affected females and males, respectively. Haplotypes for subjects who were genotyped are given under the symbols. The disease-linked haplotype is boxed. Genotypes of microsatellite markers are as published previously (Eyre et al. 2002). The marker order (top to bottom) is D15S205, AGC1 intron 1 SNP, AGC1 VNTR, AGC1 exon 18 SNP, D15S116, and D15S1004. The American Journal of Human Genetics 2005 77, 484-490DOI: (10.1086/444401) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 2 Structure of the human AGC1 gene. A, Genomic organization of the AGC1 gene. Introns are represented by horizontal lines, exons are shown as vertical lines. Intron and exon sizes are shown in kb. B, cDNA structure of the AGC1 gene, showing the location of the exons. Exon sizes are shown in bp. The translation start and stop codons are labeled with ATG and TGA, respectively. The untranslated regions are shaded. The asterisk (*) marks the single-nucleotide (C) insertion at nucleotide 4015. C, Structure of the wild-type AGC1 protein. The location of each domain is marked by the amino acid numbers, with the initiation Met as amino acid 1. CS1 and CS2 = chondroitin sulfate attachment domains 1 and 2, respectively; G1, G2, and G3 = globular domains 1, 2, and 3, respectively; IGD = interglobular domain; KS = keratan sulfate attachment domain. The position of the insertion at amino acid 1214 is indicated by an asterisk (*). D, Structure of the mutant AGC1 protein identified in the SEDK-affected family. The 212-aa missense addition at the C-terminal is represented by a wave pattern. The American Journal of Human Genetics 2005 77, 484-490DOI: (10.1086/444401) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 3 Sequence of AGC1 VNTR clones from individual IV-4, shown in reverse orientation. The division between repeats is indicated by double vertical lines, and repeat numbers are shown in bold type. Sequence variations are indicated by a shaded box around the nucleotide. A, The sequence trace shows the SNP used to distinguish the linked from the unlinked VNTR allele 3 clones. B, The sequence trace shows a 1-bp insertion of a C in the 15th repeat (arrow) in the linked but not in the unlinked allele 3. The American Journal of Human Genetics 2005 77, 484-490DOI: (10.1086/444401) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 4 Predicted translation of the normal and mutant VNTR allele 3 clones. Cysteine residues are boxed. The sequence starts at amino acid 944 of the aggrecan core protein sequence. The American Journal of Human Genetics 2005 77, 484-490DOI: (10.1086/444401) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 5 Products of the in vitro transcription and translation of normal and mutant VNTR allele 3 clones after separation by SDS-PAGE under reducing conditions. A, Translation in the presence of radiolabled 14C–amino acid mix. Lane 1, luciferase control (Promega); lane 2, individual IV-4 normal allele 3; lane 3, individual IV-4 mutant allele 3; lane 4, individual IV-5 normal allele 4; lane 5, individual IV-5 mutant allele 3; lane 6, no-RNA template control. B, Translation in the presence of 35S-cysteine. Lane 1, luciferase control (Promega); lane 2, individual IV-4 normal allele 3; lane 3, individual IV-4 mutant allele 3; lane 4, individual IV-5 normal allele 4; lane 5, individual IV-5 normal allele 3; lane 6, no-RNA template control. The American Journal of Human Genetics 2005 77, 484-490DOI: (10.1086/444401) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 6 ARMS products after electrophoresis on a 1% (weight/volume) agarose gel. Lane 1, 1-kb ladder (Bioline). Lanes 2, 4, 6, 8, 10, and 12, the products obtained when amplified with the normal oligonucleotide. Lanes 3, 5, 7, 9, 11, and 13, the products obtained when amplified with the destabilized mutant oligonucleotide. DNA was amplified from individual IV-1 (lanes 2 and 3), individual IV-2 (lanes 4 and 5), individual IV-3 (lanes 6 and 7), individual IV-4 (lanes 8 and 9), individual IV-5 (lanes 10 and 11), and individual IV-6 (lanes 12 and 13). The American Journal of Human Genetics 2005 77, 484-490DOI: (10.1086/444401) Copyright © 2005 The American Society of Human Genetics Terms and Conditions