Am J Hum Genet. 2005 Sep;77(3):484-90. Epub 2005 Jul 22.
A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis.
Gleghorn L1, Ramesar R, Beighton P, Wallis G.
The Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Manchester, United Kingdom.
Spondyloepiphyseal dysplasia (SED) encompasses a heterogeneous group of disorders characterized by shortening of the trunk and limbs. The autosomal dominant SED type Kimberley (SEDK) is associated with premature degenerative arthropathy and has been previously mapped in a multigenerational family to a novel locus on 15q26.1. This locus contains the gene AGC1, which encodes aggrecan, the core protein of the most abundant proteoglycan of cartilage. We screened AGC1 for mutations and identified a single-base-pair insertion, within the variable repeat region of exon 12 in affected individuals from the family with SEDK, that introduces a frameshift of 212 amino acids, including 22 cysteine residues, followed by a premature stop codon. This is the first identification of an AGC1 mutation causing a human disorder. This finding extends the spectrum of mutated genes that may cause SED and thus will aid in the molecular delineation of this complex group of conditions.
10.1086/444401
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. ). The marker order (top to bottom) is D15S205, AGC1 intron 1 SNP, AGC1 VNTR, AGC1 exon 18 SNP, D15S116, and D15S1004.
A Mutation in the Variable Repeat Region of the Aggrecan Gene (AGC1) Causes a Form of Spondyloepiphyseal Dysplasia Associated with Severe, Premature Osteoarthritis
Am J Hum Genet. 2005 Sep;77(3):484-490.
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.
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.
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.
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.
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).
Aggrecans
Frameshift Mutation/genetics*
Gene Components
Genetic Predisposition to Disease/genetics*
Minisatellite Repeats/genetics
Osteoarthritis/genetics*
Osteochondrodysplasias/genetics*
Proteoglycans/genetics*
ACAN protein, human
Proteoglycans
Spondyloepiphyseal dysplasia - Genetic Alliance
ACAN gene - Genetics Home Reference
Osteoarthritis - MedlinePlus Health Information
MalaCards for spondyloepiphyseal dysplasia, kimberley type - The Weizmann Institute of Science GeneCards and MalaCards databases
KEGG: Data: Disease Annotation - SciCrunch