家族性中枢性性早熟与 DLK1 缺乏有关：新的遗传学发现及血清 DLK1 水平的相关性。
Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels.
机构信息
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, 05403-000, Brazil.
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 021115, United States.
出版信息
Eur J Endocrinol. 2023 Sep 1;189(3):422-428. doi: 10.1093/ejendo/lvad129.
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.
背景
几种罕见的 delta 样非典型 notch 配体 1（DLK1）的失功能突变已在非综合征性家族性中枢性性早熟（CPP）的儿童中被描述。
目的
我们研究了法国特发性 CPP 患儿中 DLK1 基因突变。此外，我们还研究了 CPP 患者和青春期健康儿童以及野生型雌性小鼠中 DLK1 血清水平的变化模式。
患者和方法
从 121 例法国 CPP 指数病例中获得基因组 DNA。对所有病例进行 DLK1 基因编码区的自动测序。采用酶联免疫吸附试验（ELISA）法检测 209 例个体的血清 DLK1 水平，包括 191 例正常青春期发育和雌性小鼠在产后青春期成熟过程中的血清 DLK1 水平。
结果
我们在 2 例 CPP 女孩中发现了 2 种罕见的致病性 DLK1 等位基因突变：一个无义突变（c.372C>A；p.Cys124X）和一个起始缺失突变（c.2T>G；p.Met1?，或 p.0）。健康儿童和特发性 CPP 儿童的血清 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（P=0.008 和 0.016）。野生型雌性小鼠的血清 Dlk1 水平也下降。
结论
在 2 例 CPP 法国女孩中发现了 DLK1 基因的新的失功能突变。此外，我们在人类和小鼠的青春期阶段证实了循环 DLK1 血清水平的动态变化模式，这加强了该因素在青春期时间上的作用。
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