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 children's bones. Consequently, mutations in genes that regulate growth plate chondrogenesis cause abnormal bone growth in children. For genetic abnormalities that impair growth plate function, the clinical phenotype can range from chondrodysplasias with short, malformed bones to severe, often disproportionate, short stature, to mild, proportionate short stature. For genetic defects that promote growth plate function, the phenotype can include extreme, often disproportionate, tall stature. If the genetic abnormality affects tissues other than the growth plate cartilage, the child may present with a more complex syndrome that includes other clinical abnormalities. For example, growth-promoting genetic defects can present with generalized overgrowth involving multiple tissues, cognitive impairment, and increased risk of malignancy. 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, transcription factors such as SOX9, and microRNAs. 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 have used 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 helped elucidate the roles of ACAN, QRICH1, BRF1, and CYP26A1/C1 in disorders of human growth. We also discovered that neomorphic variants in SP7 cause a high-turnover bone disorder and that variants in DLG2 cause delayed puberty and contribute to isolated hypogondotropic hypogonadism. We recently studied a child with generalized overgrowth of prenatal onset. Exome sequencing identified a hemizygous frameshift variant in Spindlin 4 (SPIN4), with X-linked inheritance. We found evidence that SPIN4 binds specific histone modifications, promotes canonical WNT signaling, and inhibits cell proliferation in vitro and that the identified frameshift variant had lost all of these functions. Ablation of Spin4 in mice recapitulated the human phenotype with generalized overgrowth, including increased longitudinal bone growth. Growth plate analysis revealed increased cell proliferation in the proliferative zone and an increased number of progenitor chondrocytes in the resting zone. We also found evidence of decreased canonical Wnt signaling in growth plate chondrocytes, providing a potential explanation for the increased number of resting zone chondrocytes. Taken together, our findings provide strong evidence that SPIN4 is an epigenetic reader that negatively regulates mammalian body growth, and that loss of SPIN4 causes an overgrowth syndrome in humans, expanding our knowledge of the epigenetic regulation of human growth.