Abstract
In recent years, massively parallel sequencing technologies have helped us to identify
novel disease genes and solve the mysteries behind rare diseases. Today, we know that
some diseases with many overlapping and distinct clinical features, as presented in
this review, can be caused by mutations in genes that encode enzymes playing crucial
roles at different steps of the exact same pathway. In this review, we exclusively
focused on 5 genes – XYLT1, XYLT2, B4GALT7, B3GALT6, and B3GAT3 – that encode enzymes involved in the biosynthesis of the common tetrasaccharide
linker region of proteoglycans and review the associated diseases, also referred to
as linkeropathies, by summarizing the cases reported in literature. Since proteoglycans
are essential macromolecules in development, signaling and homeostasis of many tissues
and organs, mutations in these genes can affect many organs; including bone, cartilage,
eyes, ears, heart, and skin. Short stature, developmental delay, facial dysmorphism,
and skeletal dysplasias are some of the common features observed in patients with
mutations in these genes. Among these genes, XYLT2 mutations cause a relatively distinct phenotype, the so-called spondyloocular syndrome,
which is characterized by clinical presentation of a very severe childhood-onset primary
osteoporosis, cataract, and hearing impairment. The full phenotype spectrum of diseases
mentioned here is likely to expand with additional clinical reports and further molecular
studies.
Key words
skeletal dysplasia - glycosaminoglycan - spondyloocular syndrome - osteoporosis -
Ehlers-Danlos syndrome
