ArticleAmerican journal of human genetics2009
A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan.
Article in American journal of human genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers, 1 of them a synthesis that pooled it.
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Who cites it
76 citing papers in PubMed, 1 synthesis or guideline pooled it, 146 citations in OpenAlex.
- Research progress of short stature and advanced bone age, early-onset osteoarthritis and osteochondritis dissecans (SSOAOD) caused by acan gene mutation.Frontiers in endocrinology · 2026Pooled it
- Aggrecanopathy as an Underrecognized Cause of Idiopathic Short Stature: The Importance of Early Genetic Confirmation for Timely Diagnosis and Management-Case Reports and Literature Review.Diseases (Basel, Switzerland) · 2026Article
- The Clinical Utility of Whole-Exome Sequencing in the Prenatal Diagnosis of Fetal Skeletal Dysplasia.International journal of women's health · 2026Article
- Expanding the molecular spectrum of aggrecanopathies: exploring 24 patients with ACAN significant variants.European journal of human genetics : EJHG · 2025Article
- The genetic basis of human height.Nature reviews. Genetics · 2025Review
- Isolation and tracing of matrix-producing notochordal and chondrocyte cells using ACAN-2A-mScarlet reporter human iPSC lines.Science advances · 2024Article
- A monoallelic variant in CCN2 causes an autosomal dominant spondyloepimetaphyseal dysplasia with low bone mass.Bone research · 2024Article
- Short Stature in Klinefelter Syndrome From Aggrecan Mutation.JCEM case reports · 2024Article
- Involvement of kinesins in skeletal dysplasia: a review.American journal of physiology. Cell physiology · 2024Review
- Genotype and phenotype in patients with ACAN gene variants: Three cases and literature review.Molecular genetics & genomic medicine · 2024Review
- Aggrecan-related bone disorders; a novel heterozygous ACAN variant associated with spondyloepimetaphyseal dysplasia expanding the phenotypic spectrum and review of literature.Journal, genetic engineering & biotechnology · 2024Article
- Proteoglycan Dysfunction: A Common Link Between Intervertebral Disc Degeneration and Skeletal Dysplasia.Neurospine · 2024Article
- A Case of Short Stature Caused by a Mutation in theMolecular syndromology · 2023Article
- Case report: A novel heterozygous frameshift mutation ofFrontiers in genetics · 2023Article
- Aggrecan governs intervertebral discs development by providing critical mechanical cues of the extracellular matrix.Frontiers in bioengineering and biotechnology · 2023Article
- Growth plate extracellular matrix defects and short stature in children.Annals of pediatric endocrinology & metabolism · 2022Article
- ACAN biallelic variants in a girl with severe idiopathic short stature.Journal of human genetics · 2022Article
- Review
- Novel Insights Into the Genetic Causes of Short Stature in Children.TouchREVIEWS in endocrinology · 2022Review
- Identification of variants in ACAN and PAPSS2 leading to spondyloepi(meta)physeal dysplasias in four Chinese families.Molecular genetics & genomic medicine · 2022Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Analysis of a nuclear family with three affected offspring identified an autosomal-recessive form of spondyloepimetaphyseal dysplasia characterized by severe short stature and a unique constellation of radiographic findings. Homozygosity for a haplotype that was identical by descent between two of the affected individuals identified a locus for the disease gene within a 17.4 Mb interval on chromosome 15, a region containing 296 genes. These genes were assessed and ranked by cartilage selectivity with whole-genome microarray data, revealing only two genes, encoding aggrecan and chondroitin sulfate proteoglycan 4, that were selectively expressed in cartilage. Sequence analysis of aggrecan complementary DNA from an affected individual revealed homozygosity for a missense mutation (c.6799G --> A) that predicts a p.D2267N amino acid substitution in the C-type lectin domain within the G3 domain of aggrecan. The D2267 residue is predicted to coordinate binding of a calcium ion, which influences the conformational binding loops of the C-type lectin domain that mediate interactions with tenascins and other extracellular-matrix proteins. Expression of the normal and mutant G3 domains in mammalian cells showed that the mutation created a functional N-glycosylation site but did not adversely affect protein trafficking and secretion. Surface-plasmon-resonance studies showed that the mutation influenced the binding and kinetics of the interactions between the aggrecan G3 domain and tenascin-C. These findings identify an autosomal-recessive skeletal dysplasia and a significant role for the aggrecan C-type lectin domain in regulating endochondral ossification and, thereby, height.
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