Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Millet Cad. Çapa/Fatih, 34096, Istanbul, Turkey.
Department of Pediatric Endocrinology and Diabetes, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
J Endocrinol Invest. 2024 Aug;47(8):2041-2052. doi: 10.1007/s40618-023-02300-3. Epub 2024 Feb 17.
Central precocious puberty (CPP) is characterized by the early onset of puberty and is associated with the critical processes involved in the pubertal switch. The puberty-related gene pool in the human genome is considerably large though few have been described in CPP. Within those genes, the genomic imprinting features of the MKRN3 and DLK1 genes add additional complexity to the understanding of the pathologic pathways. This study aimed to investigate the molecular etiology in the CPP cohort.
Eighteen familial CPP cases were investigated by Sanger sequencing for five CPP-related genes; DLK1, KISS1, KISS1R, MKRN3, and PROKR2. Segregation analysis was performed in all patients with pathogenic variants. Using an ELISA test, the functional pathogenicity of novel variants was also investigated in conjunction with serum delta-like 1 homolog (DLK1) concentrations.
In three probands, a known variant in the MKRN3 gene (c.982C>T/p.(Arg328Cys)) and two novel variants in the DLK1 gene (c.357C>G/p.(Tyr119Ter) and c.67+78C>T) were identified. All three were inherited from the paternal allele. The individuals carrying the DLK1 variants had low detectable DLK1 levels in their serum.
The frequencies were 5.5% (1/18) for MKRN3 11% (2/18) for DLK1, and none for either KISS1, KISS1R, and PROKR2. Low serum DLK1 levels in affected individuals supported the relationship between here described novel DLK1 gene variants with CPP. Nonsense nature of c.357C>G/p.(Tyr119Ter) and an alteration in the evolutionarily conserved nucleotide c.67+78C>T suggested the disruptive nature of the variant's compatibility with CPP.
中枢性性早熟（CPP）的特征是青春期提前开始，并与青春期转变所涉及的关键过程有关。尽管在 CPP 中已经描述了少数几个基因，但人类基因组中与青春期相关的基因库相当大。在这些基因中，MKRN3 和 DLK1 基因的基因组印记特征为理解病理途径增加了额外的复杂性。本研究旨在调查 CPP 队列中的分子病因。
对 18 个家族性 CPP 病例进行了 5 个 CPP 相关基因（DLK1、KISS1、KISS1R、MKRN3 和 PROKR2）的 Sanger 测序。对所有具有致病性变异的患者进行了分离分析。使用 ELISA 检测，还结合血清 delta-like 1 同源物（DLK1）浓度，研究了新变异的功能致病性。
在 3 个先证者中，发现了 MKRN3 基因（c.982C>T/p.(Arg328Cys)）中的一个已知变异和 DLK1 基因中的两个新变异（c.357C>G/p.(Tyr119Ter)和 c.67+78C>T）。这三个变异均来自父系等位基因。携带 DLK1 变异的个体其血清中可检测到的 DLK1 水平较低。
MKRN3 的频率为 5.5%（1/18），DLK1 的频率为 11%（2/18），而 KISS1、KISS1R 和 PROKR2 均未发现。受影响个体血清中 DLK1 水平低支持此处描述的新 DLK1 基因突变与 CPP 之间的关系。c.357C>G/p.(Tyr119Ter)的无义性质和进化上保守核苷酸 c.67+78C>T 的改变表明变异与 CPP 的兼容性具有破坏性。
