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。对于损害生长板功能的遗传异常，临床表型的范围可以从软骨发育不良伴短的畸形骨到严重的通常不成比例的身材矮小，再到轻度的成比例的身材矮小。对于促进生长板功能的遗传缺陷，表型可以包括极端的、通常不成比例的高个子。如果遗传异常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。例如，促进生长的遗传缺陷可以表现为涉及多个组织的全身性过度生长、认知障碍和恶性肿瘤风险增加。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。以前，我们的小组研究了FGF，BMP，C型利钠肽，类维生素A，WNT，PTHrP/IHH，IGF，雌激素，糖皮质激素，转录因子如SOX 9和microRNA对生长板的调节。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，我们使用了强大的遗传方法，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，我们以前帮助阐明了ACAN，QRICH 1，BRF 1和CYP 26 A1/C1在人类生长障碍中的作用。我们还发现SP 7中的新变体导致高转换骨疾病，DLG 2中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孩子与广泛的过度生长的产前发作。外显子组测序鉴定了Spindlin 4（SPIN 4）中的半合子移码变体，具有X连锁遗传。我们发现SPIN 4结合特异性组蛋白修饰，促进经典WNT信号传导，并抑制体外细胞增殖的证据，并且鉴定的移码变体已经失去了所有这些功能。在小鼠中消融Spin 4重现了具有全身性过度生长的人类表型，包括纵向骨生长增加。生长板分析显示增殖区的细胞增殖增加，静止区的祖软骨细胞数量增加。我们还发现了生长板软骨细胞中典型Wnt信号减少的证据，为静息区软骨细胞数量增加提供了一个潜在的解释。总之，我们的研究结果提供了强有力的证据，证明SPIN 4是一种负调节哺乳动物身体生长的表观遗传阅读器，SPIN 4的缺失会导致人类过度生长综合征，扩大了我们对人类生长的表观遗传调节的知识。

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.