Regulation Of Childhood Growth

孩子长得高是因为他们的骨头长得长。这种骨骼的延长发生在生长板上，生长板是儿童骨骼末端附近的一层薄薄的软骨。因此，调节生长板软骨形成的基因突变会导致儿童骨骼生长异常。根据特定的遗传异常，临床表型可以从软骨发育不良伴短、畸形骨，到严重的、通常不成比例的身材矮小，再到轻度的成比例身材矮小。如果遗传缺陷影响生长板软骨以外的组织，儿童可能会出现更复杂的综合征，包括其他临床异常。对于许多患有生长障碍的儿童，病因仍然未知。 生长板的生长受多种相互作用的调节系统控制，包括内分泌、旁分泌、细胞外基质相关和细胞内途径。在此之前，我们的小组已经研究了FGF、BMP、C型利钠肽、类维生素A、WNTs、PTHrP/IHH、IGF、雌激素、糖皮质激素和microRNA对生长板的调节。最近，我们已经证明，SOX 9，转录因子，调节生长板软骨细胞转分化成骨细胞。在以前的其他工作中，我们研究了导致骨生长在生命早期迅速发生，但随后随着年龄的增长逐渐减慢并最终停止的机制。我们发现，与较小的骨骼相比，导致生长板功能下降的发育程序在较大的骨骼中发挥得更慢，并且这种差异性衰老导致骨骼长度的差异，从而建立正常的哺乳动物骨骼比例。 为了发现骨骼生长障碍的新遗传原因，我们正在使用强大的遗传方法，包括SNP阵列来检测缺失，重复，嵌合和单亲二体，结合外显子组测序来检测编码区和剪接位点中的单核苷酸变异和小插入/缺失。使用这种方法，我们以前已经探索了ACAN，QRICH 1，BRF 1和CYP 26 A1/C1在人类生长障碍中的作用，还发现DLG 2的变体导致青春期延迟并导致孤立的低促性腺激素性性腺功能减退症。 我们最近研究了一个患有颅缝早闭、颅骨肥厚和长骨脆性的儿童。组织形态计量学显示成骨细胞增加，但骨矿化减少。外显子组测序确定了一个新的显性新形态错义变体，一个名为SP 7（也称为osterix）的基因是导致这种疾病的原因。SP 7是成骨细胞成熟和骨形成的关键转录因子。具有相应变体的小鼠也显示出与Sp 7缺失小鼠不同的复杂骨骼表型。该突变改变了SP 7的结合特异性，从AT丰富的基序到GC共有序列（其他SP家族成员的典型序列），并产生了异常的基因表达谱，包括Col 1a 1和内源性Sp 7的表达增加，但参与基质矿化的基因表达减少。我们的研究确定了一种新的致病机制，其中一个转录因子的突变转移DNA结合特异性，并提供了第一个体内证据表明，SP 7的亲和力AT丰富的图案，独特的SP蛋白，是正常的成骨细胞分化的关键。

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.