BACKGROUND Several rare loss-of-function mutations of delta-like noncanonical notch ligand 1 (DLK1) have been described in non-syndromic children with familial central precocious puberty (CPP). OBJECTIVE We investigated genetic abnormalities of DLK1 gene in a French cohort of children with idiopathic CPP. Additionally, we explored the pattern of DLK1 serum levels in patients with CPP and in healthy children at puberty, as well as in wild-type female mice. PATIENTS AND METHODS Genomic DNA was obtained from 121 French index cases with CPP. Automated sequencing of the coding region of the DLK1 gene was performed in all cases. Serum DLK1 levels were measured by enzyme linked immunosorbent assay (ELISA) in 209 individuals, including 191 with normal pubertal development and in female mice during postnatal pubertal maturation. RESULTS We identified 2 rare pathogenic DLK1 allelic variants: A stop gain variant (c.372C>A; p.Cys124X) and a start loss variant (c.2T>G; p.Met1?, or p.0) in 2 French girls with CPP. Mean serum DLK1 levels were similar between healthy children and idiopathic CPP children. In healthy individuals, DLK1 levels correlated with pubertal stage: In girls, DLK1 decreased between Tanner stages III and V, whereas in boys, DLK1 decreased between Tanner stages II and V (P = .008 and .016, respectively). Serum levels of Dlk1 also decreased in wild-type female mice. CONCLUSIONS Novel loss-of-function mutations in DLK1 gene were identified in 2 French girls with CPP. Additionally, we demonstrated a pattern of dynamic changes in circulating DLK1 serum levels in humans and mice during pubertal stages, reinforcing the role of this factor in pubertal timing.

中文翻译：

---

DLK1 缺乏导致的家族性中枢性性早熟：新的遗传发现和血清 DLK1 水平的相关性。

背景 已在患有家族性中枢性性早熟（CPP）的非综合征儿童中描述了几种罕见的 δ 样非典型缺口配体 1（DLK1）功能丧失突变。目的 我们调查了法国特发性 CPP 儿童队列中 DLK1 基因的遗传异常。此外，我们还探讨了 CPP 患者、青春期健康儿童以及野生型雌性小鼠中 DLK1 血清水平的模式。患者和方法 从 121 名法国 CPP 指示病例中获取基因组 DNA。在所有情况下都对 DLK1 基因编码区进行自动测序。通过酶联免疫吸附测定 (ELISA) 测量了 209 名个体的血清 DLK1 水平，其中包括 191 名青春期发育正常的个体以及出生后青春期成熟期间的雌性小鼠。结果 我们在 2 种法语中鉴定出 2 种罕见致病性 DLK1 等位基因变异：停止增益变异 (c.372C>A; p.Cys124X) 和起始丢失变异 (c.2T>G; p.Met1? 或 p.0)有 CPP 的女孩。健康儿童和特发性 CPP 儿童的平均血清 DLK1 水平相似。在健康个体中，DLK1 水平与青春期阶段相关：在女孩中，DLK1 在 Tanner III 期和 V 期之间下降，而在男孩中，DLK1 在 Tanner II 期和 V 期之间下降（分别为 P = 0.008 和 0.016）。野生型雌性小鼠中 Dlk1 的血清水平也有所下降。结论 在 2 名患有 CPP 的法国女孩中发现了新的 DLK1 基因功能丧失突变。此外，我们还证明了人类和小鼠在青春期阶段循环 DLK1 血清水平的动态变化模式，强化了该因素在青春期时机中的作用。