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Mutations in the prolyl 3-hydroxylation complex member, CRTAP, were first described in a rare form of osteogenesis imperfecta (OI type VII) and in a recessively inherited form of OI type III. They highlighted the significance of this post-translational modification in the pathogenesis of recessive OI. Since this initial discovery, patients with mutations in all three genes encoding the proteins that form the prolyl 3-hydroxylase complex, LEPRE1, CRTAP, and PPIB, have been identified. Studies in humans and mice have also shown that in addition to its role as a prolyl 3-hydroxylase, the complex also functions as a cis-trans isomerase and a collagen chaperone. The focus of this chapter is to provide a historical perspective of the discoveries pertaining to the prolyl 3-hydroxylation complex and what we have learned about the contribution of the complex towards the pathogenesis of disease.

Publisher Summary Nail-patella syndrome (NPS) is a dominantly inherited malformation syndrome that affects multiple organs including the skeleton, nails, eyes, and kidneys. The skeletal dysplasia of NPS includes abnormalities of the knees, elbows, pelvis, and feet. Primary open-angle glaucoma (POAG) has been shown to cosegregate with NPS in some families and is now considered a variable feature of NPS. The renal disease that accompanies NPS has the greatest impact on long-term morbidity and mortality. Renal symptoms can start at any age and most often begin as microalbuminuria with or without hematuria. Proteinuria can be intermittent and may present during or be exacerbated by pregnancy. Mutations in the LMX1Bgene cause NPS. NPS was one of the first Mendelian conditions mapped by linkage using ABO blood groups. NPS is associated with a variety of orthopedic problems including chronic problems with elbows and knees and foot abnormalities. The LMX1B protein contains, from the N-terminus to the C-terminus, four distinct functional domains, two LIM domains, LIM-A and LIM-B that are important for protein-protein interactions, a homeodomain important for DNA binding, and a glutamine-rich and serine-rich domain with putative transcriptional activation functions. The skeletal features of NPS likely reflect a relative loss of Lmx1bspecification of dorsal patterning of the limb mesenchyme. This is best exemplified by the hypoplasia of the patella, an embryologic dorsal element of hindlimb morphogenesis. At the same time, dorsal-ventral patterning is intimately linked to establishment of anterior-posterior pattern. The persistence of Lmx1bexpression in distal limb mesenchymal derivatives in a graded pattern across the A/P axis is reflected in the nail dysplasia that is often more severe in the anterior digits.