Regulation Of Childhood Growth

孩子长高是因为他们的骨骼长得更长。这种骨骼伸长发生在生长板上，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异常生长。对于损害生长板功能的遗传异常，临床表现可从伴有短骨畸形的软骨发育不良到严重的、通常不成比例的矮小，再到轻微的、成比例的矮小。对于促进生长板功能的遗传缺陷，表型可能包括极端的、通常不成比例的高个子。如果遗传异常影响到生长板软骨以外的其他组织，儿童可能会出现更复杂的综合征，其中包括其他临床异常。例如，促进生长的基因缺陷可表现为累及多个组织的广泛性过度生长、认知障碍和恶性风险增加。对于许多患有生长障碍的儿童来说，病因尚不清楚。 生长板的生长受多个相互作用的调节系统控制，涉及内分泌、旁分泌、细胞外基质相关和细胞内途径。在此之前，我们的团队已经研究了FGFs、BMPs、C型利钠肽、维甲酸、WNTs、PTHrP/IHH、IGFS、雌激素、糖皮质激素、转录因子如SOX9和microRNAs对生长板的调控。在其他以前的工作中，我们研究了导致骨生长在早期迅速发生，但随后随着年龄增长逐渐放缓并最终停止的机制。我们发现，导致生长板功能下降的发育程序在较大的骨骼中比在较小的骨骼中发挥得更慢，这种不同的衰老导致了骨骼长度的差异，从而建立了正常的哺乳动物骨骼比例。 为了发现骨骼生长障碍的新的遗传原因，我们使用了强大的遗传方法，包括SNP阵列来检测缺失、重复、嵌合体和单亲二体，结合外显子测序来检测编码区和剪接点的单核苷酸变异和小插入/缺失。利用这种方法，我们以前帮助阐明了ACAN、QRICH1、BRF1和CYP26A1/C1在人类生长障碍中的作用。我们还发现，SP7中的新形变异体导致高转换性骨骼疾病，DLG2中的变异体导致青春期延迟，并导致孤立的低促性腺激素减退症。 我们最近研究了一名出生前普遍发育过度的儿童。外显子组测序发现Spindlin 4(SPIN4)有一个半合子移码突变，具有X连锁遗传。我们发现有证据表明，SPIN4结合特定的组蛋白修饰，促进规范的WNT信号，并在体外抑制细胞增殖，并且已发现的移码变异体已经失去了所有这些功能。在小鼠身上切除Spin4重现了人类普遍过度生长的表型，包括增加了纵向骨生长。生长板分析显示增殖区细胞增殖增加，静止区前体软骨细胞数量增加。我们还发现生长板软骨细胞中典型的Wnt信号减少的证据，这为静止区软骨细胞数量的增加提供了一个潜在的解释。综上所述，我们的发现提供了强有力的证据，表明SPIN4是一个负向调节哺乳动物身体生长的表观遗传阅读器，而SPIN4的缺失会导致人类的过度生长综合征，扩大了我们对人类生长的表观遗传调控的知识。

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.