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.

Keywords: ciliopathy; epigenetics; growth insufficiency; imprinting; mosaicism; primordial dwarfism.

Figure 1. Overview of the growth plate

Cells within the resting, proliferative, and hypertrophic zones of the growth plate have a distinctive morphology and organization, which is visible in a section through a three-week-old mouse growth plate stained with eosin and hematoxylin (left). The Notch, WNT, FGF, Hedgehog, and BMP signaling pathways act on the cells of the growth plate (right). Arrows indicate activation of one pathway by another, and lines with a bar at the end indicate inhibition of the pathway. Blue lines indicate crosstalk between pathways. For example, PI3K is thought to affect the CNP, IHH, and PTHrP signaling pathways. Many of these pathways have been implicated in multiple skeletal dysplasias. The arrows underneath the names of the resting and proliferative zones indicate the orientation of cell division within these zones. Abbreviations: BMP, bone morphogenetic protein; CNP, C-type natriuretic peptide; FGF, fibroblast growth factor; IHH, Indian Hedgehog; PCP, planar-cell polarity; PI3K, phosphoinositide 3-kinase; PTHrP, parathyroid hormone–related peptide.

Figure 2. Cellular pathways disrupted in primordial dwarfism

Most genes implicated in primordial dwarfism (MGS, MOPD I and II, Seckel syndrome, and SOFT syndrome) are involved in cell cycle regulation and cell division. These processes include primary ciliogenesis (G₁ phase), DNA replication and centrosome duplication (S phase), DNA repair and centrosome maturation (G₂ phase), and mitotic spindle formation and mitosis (M phase). Many of the genes function in more than one phase of the cell cycle. Some genes affect the rate of progression through the cell cycle, and some lead to aneuploidy, probably due to defects in DNA repair or mitotic spindle formation. In some cases, the cell cycle becomes disrupted after several rounds of cell division owing to disturbances in centriole duplication and/or maturation. All the processes shown involve replication and repair or maturation of the genome and the centrosome except RNU4ATAC. RNU4ATAC has a critical role in splicing, which could affect genes involved in cell cycle regulation or division. Abbreviations: MGS, Meier-Gorlin syndrome; MOPD, microcephalic osteodysplastic primordial dwarfism; MPD, microcephalic primordial dwarfism; SOFT, short stature, onychodysplasia, facial dysmorphism, and hypotrichosis.

Figure 3. Primary cilium proteins implicated in skeletal dysplasias

Components of the primary cilium are disrupted in many forms of skeletal dysplasia. These components include genes that encode parts of motor proteins (e.g., dynein) and parts of both the IFT-A and IFT-B complexes, which regulate retrograde and anterograde ciliary trafficking, respectively. The colors of the cilium components signify the types of disorders with which they are associated.