May 2013

Bone and skin disorders caused by disruptions in GAG synthesis

biosynthetic assembly of the GAG backbones 
Fig. 1 from the Mizumoto et al minireview shows a schematic presentation of the biosynthetic assembly of the GAG backbones by various glycosyltransferases. Click on the image to see a larger, more easily readable version of it. 

A number of bone and skin disorders that cause disfiguration, pain and sometimes premature death are rooted in genetic mutations that disrupt the synthesis of sulfated glycosaminoglycans, also known as GAGs.
For example, Larsen-like syndrome results in joint displacement and heart defects and is caused by mutation of β1,3-glucuronosyltransferase-I, reducing GAG production. Another disease, Omani-type spondyloepiphyseal dysplasia, results from mutation in chondroitin 6-O-sulfotransferase-1 and is characterized by shortness, joint disturbances, abnormal spine curvature, mild digit shortness, fusion of the carpal bones, altered limb length, heart defects and deafness.
In a recent minireview in The Journal of Biological Chemistry, Kazuyuki Sugahara at Hokkaido University in Japan and colleagues focus on two types of GAGs, chondroitin and dermatan sulfate, and what we know about their roles in bone and skin disorders.
To start, the authors cover the biosynthesis of chondroitin sulfate and dermatan sulfate side chains. They describe the steps of GAG synthesis: 1) the addition of a tetrasaccharide linkage region that connects the various GAGs to a serine in the core protein; 2) the addition of N-acetyl-D-galactosamine, which signals the construction of chondroitin sulfate or dermatan sulfate, or the addition of N-acetyl-D-glucosamine, which initiates the assembly of heparan sulfate; 3) elongation via the addition of repeating disaccharide units; and 4) the sulfation of these chains, which differs among various cell and tissue types, developmental states and diseases. A host of enzymes is involved with the synthesis of these diverse side chains, and their mutations can lead to a variety of diseases.
Ehlers-Danlos syndrome-progeroid type is caused by a β1, 4-galactosyltransferase-I deficiency and results in skin and bone disturbances, including shortness, osteopenia and an older physical appearance. The disease characteristics are mainly caused by disruptions in dermatan sulfate chains.
The authors also comment on disruptions to the β1, 4-N-acetylgalactosaminyltransferase-I and II enzyme activities as seen in Bell’s palsy and some hereditary motor and sensory neuropathies. These conditions involve partial facial paralysis (Bell’s palsy) and the ongoing loss of peripheral sensory nerve function leading to collapses and muscle weakness (hereditary motor and sensory neuropathies).
Another disease resulting from GAG synthesis enzyme mutations is Temtamy pre-axial brachydactyly syndrome. The enzyme affected is chondroitin synthase 1, and its mutation results in digit and facial deformities, hearing impairments, developmental delay and shortness.
The authors also mention adducted thumb-clubfoot syndrome, which results from mutations to a gene that encodes dermatan 4-O-sulfotransferase-1, causing increased production of chondroitin sulfate over dermatan sulfate.
While a lot has been learned about GAG function and synthesis in the past 15 years thanks to the cloning of cDNAs for the genes encoding GAG synthesis enzymes and thanks to collaborations among clinicians, geneticists and glycobiologists, the authors write, “further understanding of the molecular pathogenesis involving (chondroitin sulfate and dermatan sulfate) chains is essential to facilitate the development of therapeutics for these diseases.”

Danielle GutierrezDanielle Gutierrez ( is a freelance science writer based in Corpus Christi, Texas.

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