Regulation Of Childhood Growth

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

Children grow taller because their bones grow longer. This bone elongation occurs at the growth plate, a thin layer of cartilage found near the ends of childrens bones. Consequently, mutations in genes that regulate growth plate chondrogenesis cause abnormal bone growth in children. Depending on the specific genetic abnormality, the clinical phenotype can range from chondrodysplasias with short, malformed bones, to severe, often disproportionate, short stature, to mild proportionate short stature. If the genetic defect affects tissues other than the growth plate cartilage, the child may present with a more complex syndrome that includes other clinical abnormalities. For many children with growth disorders, the etiology remains unknown. Growth at the growth plate is controlled by multiple interacting regulatory systems, involving endocrine, paracrine, extracellular matrix-related, and intracellular pathways. Previously, our group has studied growth plate regulation by FGFs, BMPs, C-type natriuretic peptide, retinoids, WNTs, PTHrP/IHH, IGFs, estrogens, glucocorticoids, and microRNAs. More recently, we have shown evidence that SOX9, a transcription factor, regulates the transdifferentiation of growth plate chondrocytes into osteoblasts. In other previous work, we investigated the mechanisms that cause bone growth to occur rapidly in early life but then to progressively slow with age and eventually cease. We showed that the developmental program responsible for the decline in growth plate function plays out more slowly in larger bones compared to smaller bones and that this differential aging contributes to the disparities in bone length and therefore to establishing normal mammalian skeletal proportions. To discover new genetic causes of skeletal growth disorders, we are using powerful genetic approaches including SNP arrays to detect deletions, duplications, mosaicism, and uniparental disomy, combined with exome sequencing to detect single nucleotide variants and small insertions/deletions in coding regions and splice sites. Using this approach, we have previously explored the roles of ACAN, QRICH1, BRF1, and CYP26A1/C1 in disorders of human growth and also discovered that variants in DLG2 cause delayed puberty and contribute to isolated hypogondotropic hypogonadism. We recently studied a child with craniosynostosis, cranial hyperostosis, and long bone fragility. Histomorphometry showed increased osteoblasts but decreased bone mineralization. Exome sequencing identified a de novo dominant neomorphic missense variant a gene called SP7 (also known as osterix) as the cause of the disorder. SP7 is a transcription factor critical for osteoblast maturation and bone formation. Mice with the corresponding variant also showed a complex skeletal phenotype distinct from that of Sp7-null mice. The mutation altered the binding specificity of SP7 from AT-rich motifs to a GC-consensus sequence (typical of other SP family members) and produced an aberrant gene expression profile, including increased expression of Col1a1 and endogenous Sp7, but decreased expression of genes involved in matrix mineralization. Our study identifies a novel pathogenic mechanism in which a mutation in a transcription factor shifts DNA binding specificity and provides the first in vivo evidence that the affinity of SP7 for AT-rich motifs, unique among SP proteins, is critical for normal osteoblast differentiation.