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Mutagenesis and Analysis of Genetic Mutations in the GC-rich KISS1 Receptor Sequence Identified in Humans with Reproductive Disorders
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Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations
Carlos Eduardo Seraphim1, Ana Pinheiro Machado Canton1, Luciana Montenegro1
1Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
The Journal of Clinical Endocrinology and Metabolism
|December 31, 2020
Summary
Loss-of-function mutations in makorin RING finger protein 3 (MKRN3) cause familial central precocious puberty (CPP). Genetic defects impact bone age and gonadotropin levels, though clinical presentation is similar to idiopathic CPP.
Area of Science:
- Endocrinology
- Genetics
- Pediatrics
Background:
- Loss-of-function mutations in makorin RING finger protein 3 (MKRN3) are the primary genetic cause of familial central precocious puberty (CPP).
- Understanding the clinical and hormonal spectrum associated with MKRN3 mutations is crucial for accurate diagnosis and management.
Purpose of the Study:
- To characterize the clinical and hormonal features of a large cohort of patients with CPP resulting from MKRN3 mutations.
- To compare the characteristics of different types of genetic defects within MKRN3.
Main Methods:
- A multiethnic cohort of 716 patients with familial or idiopathic CPP underwent screening for MKRN3 mutations via Sanger sequencing.
- A control group of 156 Brazilian girls with idiopathic CPP (ICPP) was included for comparison.
Main Results:
- Eighteen distinct loss-of-function MKRN3 mutations were identified in 71 patients (45 girls, 26 boys).
- Severe MKRN3 mutations correlated with greater bone age advancement and higher basal luteinizing hormone levels compared to missense mutations.
- Girls with MKRN3 mutations exhibited earlier puberty onset and elevated follicle-stimulating hormone levels compared to the ICPP control group.
Conclusions:
- Inherited premature activation of the reproductive axis due to MKRN3 mutations presents clinically similarly to idiopathic CPP.
- The specific type of MKRN3 genetic defect can influence bone age maturation and gonadotropin levels, highlighting the importance of genetic analysis.
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