A novel gene (FAM20B encoding glycosaminoglycan xylosylkinase) for neonatal short limb dysplasia resembling Desbuquois dysplasia.

Desbuquois dysplasia (DBQD) is an autosomal recessive heterogeneous disorder characterized by joint laxity and skeletal changes, including a distinctive monkey-wrench appearance of the femora, advanced carpal ossification, and abnormal patterning of the preaxial digits. Two genes for DBQD (CANT1 encoding calcium-activated nucleotidase-1 and XYLT1 encoding xylosyltransferase-1) have been reported. We propose a novel gene for neonatal short limb dysplasia resembling DBQD, based on the phenotype and genotype of two affected siblings. The affected boy and girl died in early infancy and shortly after birth, respectively. The clinical hallmarks included mid-face hypoplasia, thoracic hypoplasia with respiratory failure, very short stature (approximately -7 SD of birth length) with mesomelic shortening of the limbs, and multiple dislocations of the large joints. Radiological examinations showed prominent lesser trochanter, flared metaphyses of the long bones, and joint dislocations. The affected boy had preaxial digital hypoplasia, and the affected girl showed overlapping and syndactyly of the preaxial digits. Molecular analyses of the girl showed compound heterozygous variants in FAM20B (NM_014864: c.174_178delTACCT p.T59Afs*19/c.1038delG p.N347Mfs*4). FAM20B encodes glycosaminoglycan xylosylkinase, which acts downstream of xylosyltransferase-1. Given the fact that FAM20B deficiency causes skeletal phenotypes in mice and zebrafish, these variants are highly probable to be pathogenic.

Polydactyly in mice lacking HDAC9/HDRP.

Mice lacking histone deacetylase 9 (HDAC9) and its truncated variant, HDRP, exhibit post-axial polydactyly that manifests as an extra big toe on the right hind foot. Polydactyly in HDAC9/ HDRP knockout mice occurs with incomplete penetrance and affects both genders similarly. Because polydactyly can result from overactivity of sonic hedgehog (Shh) signaling, we investigated whether HDRP acted as a negative regulator of the Shh pathway. We find that Gli1, a transcription factor and downstream mediator of Shh signaling, is expressed at substantially higher levels in the feet of perinatal HDAC9/ HDRP-/- mice as compared with wild-type littermates. To more directly examine whether HDRP negatively-regulates Shh signaling we utilized cell lines that express components of the Shh pathway and that respond to the Shh agonist purmorphamine. We find that purmorphamine-mediated stimulation of Gli1 in the NIH 3T3 and HT22 cell lines is inhibited by the expression of HDRP. In HT22 cells, purmorphamine treatment leads to an increase in the rate of cell proliferation, which is also inhibited by HDRP. This inhibitory effect of HDRP on purmorphamine-mediated cell proliferation was also observed in primary cultures of glial cells. Although the mechanism by which it inhibits Gli1 induction and cell proliferation by purmorphamine is not clear, HDRP localizes to the nucleus suggesting it acts just upstream of Gli3 activation in the signaling cascade activated by Shh. Taken together our results suggest that HDRP acts as a negative regulator of the Shh pathway and that the absence of HDRP results in hyper-activation of this pathway resulting in polydactyly.

Mutations in Biosynthetic Enzymes for the Protein Linker Region of Chondroitin/Dermatan/Heparan Sulfate Cause Skeletal and Skin Dysplasias.

Glycosaminoglycans, including chondroitin, dermatan, and heparan sulfate, have various roles in a wide range of biological events such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Their polysaccharides covalently attach to the serine residues on specific core proteins through the common linker region tetrasaccharide, -xylose-galactose-galactose-glucuronic acid, which is produced through the stepwise addition of respective monosaccharides by four distinct glycosyltransferases. Mutations in the human genes encoding the glycosyltransferases responsible for the biosynthesis of the linker region tetrasaccharide cause a number of genetic disorders, called glycosaminoglycan linkeropathies, including Desbuquois dysplasia type 2, spondyloepimetaphyseal dysplasia, Ehlers-Danlos syndrome, and Larsen syndrome. This review focused on recent studies on genetic diseases caused by defects in the biosynthesis of the common linker region tetrasaccharide.