Advances in Skeletal Dysplasia Genetics

Abstract

Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately 1/5,000 births, and some are lethal. Since the most recent publication of the Nosology and Classification of Genetic Skeletal Disorders, genetic causes of 56 skeletal disorders have been uncovered. This remarkable rate of discovery is largely due to the expanded use of high-throughput genomic technologies. In this review, we discuss these recent discoveries and our understanding of the molecular mechanisms behind these skeletal dysplasia phenotypes. We also cover potential therapies, unusual genetic mechanisms, and novel skeletal syndromes both with and without known genetic causes. The acceleration of skeletal dysplasia genetics is truly spectacular, and these advances hold great promise for diagnostics, risk prediction, and therapeutic design.

Profilin 1 Negatively Regulates Osteoclast Migration in Postnatal Skeletal Growth, Remodeling, and Homeostasis in Mice

“…However, despite displaying altered growth plate curvature, the chondrocytes in this region did not show any alteration in the columnar alignment that we observed histologically in chondrocyte‐specific Pfn1 ‐cKO mice in a previous study . The possible involvement of osteoblastic precursor cells and osteocytes in this region was not thoroughly investigated, but the absence of alterations in growth plate chondrocytes in dwarf mice is not surprising because this is often the case in the dysplastic mutant mice and human disorders associated with impaired bone turnover and short stature . Short stature in osteopetrosis patients is a recurrent symptom, with no apparent pathological changes in growth plates.…”

Regulation of ciliary retrograde protein trafficking by the Joubert syndrome proteins ARL13B and INPP5E

“…The lack of an IFT-A or IFT-B subunit often results in extremely short or no cilia (for example, see Huangfu et al, 2003;Jonassen et al, 2008;Liem et al, 2012), implying a defect in the trafficking of proteins essential for ciliary assembly. Furthermore, mutations in some of the IFT-A and IFT-B subunits are known to cause BBS and SRTD: IFT121 (SRTD7), IFT139 (SRTD4), IFT140 (SRTD9), and IFT144 (SRTD5) of the IFT-A complex; and IFT27 (BBS19), IFT52 (SRTD16), IFT80 (SRTD2), IFT172 (BBS20 or SRTD10) of the IFT-B complex (Cortés et al, 2015;Geister and Camper, 2015).…”

A Tunable, Three-DimensionalIn VitroCulture Model of Growth Plate Cartilage Using Alginate Hydrogel Scaffolds

“…Defects in growth plate function due to genetics (inci dence of chondrodysplasia-1 in 5000 births), metabolic disease, radiation and chemotherapy, and high impact fractures affect skeletal growth, which can lead to deformities, growth arrest, or structural instability of developing long bones. [22][23][24] However, an incomplete understanding of the molecular and cellular pro cesses that produce growth has resulted in few clinical options to treat growth defects and has severely limited advances in tis sue engineering and regenerative strategies to replace damaged or diseased tissue. [22][23][24] Although genetic models have identified many important molecules that regulate cartilage morphogen esis, a deeper mechanistic understanding of growth regulation in vertebrates has been confounded by the lack of tools for pre cise and combinatorial genetic manipulation that is needed to determine mechanism.…”

“…2,5 Despite a deep understanding of the regulatory pathways that regulate growth, few options exist for clinical intervention in growth disorders. [21][22][23][24] In vitro models of growth plate car tilage that reveal the network structure of regulatory interac tions would advance both drug discovery efforts and tissue en gineering solutions for growth disorders. One challenge is that chondrocytes readily form cartilage in vitro, but they do not spontaneously assemble into functional growth plates.…”