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CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism
Ihsan Turan1, B Ian Hutchins2, Bulent Hacihamdioglu3
1Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.
The Journal of Clinical Endocrinology and Metabolism
|March 22, 2017
Summary
Inactivating CCDC141 gene variants cause idiopathic hypogonadotropic hypogonadism (IHH), a condition affecting reproductive development. These findings highlight the genetic complexity of IHH and Kallmann syndrome (KS).
Area of Science:
- Genetics
- Endocrinology
- Neuroscience
Background:
- Gonadotropin-releasing hormone (GnRH) neurons migrate from the olfactory placode to the brain, crucial for the hypothalamic-pituitary-gonadal axis.
- Failure in GnRH neuron migration causes idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS).
- Previous research linked CCDC141 gene knockdown to impaired GnRH neuron migration.
Purpose of the Study:
- To investigate the prevalence and clinical presentation of CCDC141 mutations in IHH/KS patients.
- To further elucidate the role of CCDC141 in GnRH neuron development and migration.
Main Methods:
- Autozygosity mapping, candidate gene screening, whole-exome sequencing, and Sanger sequencing were employed.
- Phenotypic data were collected from 120 IHH/KS families.
- Deleterious CCDC141 variants and associated phenotypes were identified.
Main Results:
- Inactivating CCDC141 variants were identified in 3.3% of IHH/KS families (9 individuals across 4 families).
- Affected individuals typically have normal olfactory function and olfactory bulbs, distinguishing normosmic IHH from KS.
- Clinical reversibility was observed in four affected individuals; some families showed variants in other puberty-related genes.
Conclusions:
- Inactivating CCDC141 variants are a cause of normosmic IHH, not KS.
- This confirms CCDC141's essential role in embryonic GnRH neuron migration.
- The study expands the known genetic spectrum of IHH, underscoring the complexity of genotype-phenotype correlations.
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