ACAN and Associated Diseases
Creative Biolabs is an innovative biotechnology company focused on providing innovative high-quality scientific tools for global gene therapy research. Our vision is to assist our clients to achieve exceptional success and breakthroughs in gene therapy. With extensive experience, we are delighted to provide a brief introduction to the aggrecan (ACAN) gene.
Introduction to ACAN Gene
ACAN gene belongs to the versican family and is located on chromosome 15q26. It contains 19 exons and ranges in size from 77-4224 bp. Aggrecan, encoded by the ACAN gene, is the vital polysaccharide element of the extracellular matrix (ECM) in cartilage tissue. Therefore, this protein is pivotal for the structure as well as the function of all cartilage, including growth plates during endochondral ossification. Notably, the hydrated gel structure of aggrecan is closely related to the resistance to compression in cartilage. Furthermore, aggrecan is also a crucial regulator in chondrocyte bone morphogenesis.
Fig.1 The structure of ACAN and the position of mutations. (Dateki, 2017)
ACAN Abnormality and Diseases
ACAN alterations have been implicated in many disorders, ranging from mild short stature to severe bone dysplasia. Alterations in the ACAN gene lead to a series of consequences, such as proteoglycan deficiency, abnormal structure of the ECM of chondrocytes, and accelerated chondrocyte differentiation. It has been reported that homozygous mutations caused short stature, brachydactyly, severe skeletal dysplasia, and midface hypoplasia. Heterozygous variations result in milder skeletal dysplasia known as the Kimberley type. Furthermore, since aggrecan is critical for skeletal development and cartilage function, ACAN is considered to be a key candidate gene for familial osteochondritis dissecans (fOCD) as well as early onset osteoarthritis. Additionally, increasing evidence suggests that ACAN pathogenic variants substantially contribute to the occurrence of idiopathic short stature (ISS).
Disease Mechanisms for ACAN Variants
Many ACAN variants are associated with autosomal dominant nonsense or frameshift mutations that may affect any domain of proteoglycans. These variants resulted in premature termination of translation and reduced levels of aggrecan. Naturally, the reduced levels of proteoglycans caused by these variants may also affect articular cartilage function. Currently, several ACAN gene variants have been studied in detail. For example, a missense ACAN variant is correlated with short stature and fOCD. This variant results in a single amino acid substitution in the C-type lectin repeat of the globular domain of proteoglycan G3, which affects interactions with other chondrocyte ECM components. In addition, another epiphyseal dysplasia aggrecan type (SEMD) missense variant affects the globular domain of aggrecan.
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Reference
- Dateki, S. ACAN mutations as a cause of familial short stature. Clinical Pediatric Endocrinology. 2017, 26(3): 119-125.
