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

Abstract

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.

Modern origin of numerous alternatively spliced human introns from tandem arrays

“…Last, at least 12 intron-breeding repeats identified in our study have been described as variable number of tandem repeats (VNTR) (minisatellites) and hence are highly polymorphic within the human population (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Polymorphisms in the tandem-repeat sequence of the thymidylate synthase gene are used as markers for effectiveness of 5-fluorouracil in cancer patients (42)(43)(44).…”

Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation

“…13 To date, at least 25 pathological ACAN mutations including our case have been reported. [5][6][7][8][9][10][11][12] The autosomal recessive condition in a single family was characterized by extreme short stature (66-71 cm final height) with short necks, barrel chests and craniofacial abnormalities, including macrocephaly, brachydactyly, and mid-face hypoplasia, referred as SEMD aggrecan type. 5 On the other hand, the heterozygous mutations exhibit a broad phenotypic spectrum of short stature associated with advanced bone maturation, early-onset osteoarthritis, and mild dysmorphic features including mid-facial hypoplasia, brachydactyly, broad great toes, and lumbar lordosis, with no apparent genotype-phenotype correlations.…”

“…4 To date, at least 24 pathological ACAN mutations have been identified in patients with highly variable phenotypes, such as spondyloepimetaphyseal dysplasia (SEMD) aggrecan type, spondyloepiphyseal dysplasia Kimberley type, familial osteochondritis dissecans, early-onset osteoarthritis, and short stature with advanced bone maturation. [5][6][7][8][9][10][11][12] We herein report a Japanese family with ISS with a novel heterozygous frameshift mutation in the ACAN gene (c.1744delT; p.Phe582fs*69), providing further evidence that ACAN haploinsufficiency causes short stature with advanced bone maturation. Furthermore, we advocate multiple lumbar disc herniation as a novel phenotype associated with ACAN haploinsufficiency.…”

Employing molecular genetics of chondrodysplasias to inform the study of osteoarthritis

“…A mutation in the aggrecan gene was identified in a form of human spondyloepiphyseal dysplasia associated with severe premature OA (27). This mutation has been described only in 1 South Africa Caucasian family.…”

“…The mutation is a single-base insertion within the variablenumber tandem repeat (VNTR) region of exon 12, which introduces a premature stop codon. The truncated protein lacks almost all of the chondroitin sulfate attachment region and includes a 212-amino-acid missense addition at the C-terminus (27). Recently, an autosomaldominant missense mutation was identified in a large Swedish pedigree segregating with OA dissecans and early OA (osteochondritis dissecans is defined as a separation of cartilage and subchondral bone from surrounding tissue) (28).…”