ECE2024 Poster Presentations Reproductive and Developmental Endocrinology (45 abstracts)
Congenital hypogonadotropic hypogonadism by PNPLA6 mutations: identification of a wide phenotypic spectrum and functional correlations with the NTE in vitro activity
Luigi Maione 1 , Jerome Bouligand 2 , Antoine Rousseau 3 , Salome Prevost 4 , Lydie Naule 5 , Sylvie Salenave 1 , Philippe Chanson 1 , Ursula Kaiser 6 & Jacques young 7
1Saclay University, Endocrinology and Reproductive Diseases, Le Kremlin-Bicêtre, France; 2Saclay University, Genetics, Le Kremlin-Bicêtre, France; 3Saclay University, Ophtalmology, Le Kremlin-Bicêtre, France; 4Kremlin-Bicètre, Genetics, Le Kremlin-Bicêtre, France; 5Paris, Sorbonne University, Paris, France; 6Brigham and Women’s Hospital, Boston, United States; 7Saclay University, Endocrinology and Reproductive Diseases, Le Kremlin-Bicêtre, France
Background: PNPLA6 mutations are associated with complex autosomal recessive disorders including congenital hypogonadotropic hypogonadism (CHH): Gordon-Holmes syndrome, Boucher-Neuhauser syndrome and hereditary spastic paraplegia, which include ophthalmologic and neurologic disorders in addition to CHH. PNPLA6 gene encodes the neuropathy target esterase (NTE), an endoplasmic reticulum-associated enzyme intervening in the metabolism of membrane phospholipids.
Aim: Analysis of prevalence of PNPLA6 mutations within a large cohort of CHH patients. Clinical, biological, neuroendocrine and molecular characterization of six patients from three unrelated families, carrying five PNPLA6 biallelic mutations.
Patients and Methods: Neuroendocrine profile: measurement of 4 hours-spontaneous LH pulsatility and response to bolus and repeated GnRH (by pump), neurological and ophthalmological examinations of affected patients. Assessment of the enzymatic activity on cell lysates expressing wild-type (WT) and mutant NTE.
Results: Biallelic PNPLA6 mutations are very rare (<1% among 800 exomes in CHH patients). Two brothers harbored a homozygous, four patients a composite heterozygous mutation. Phenotypic spectrum was wide, ranging from severe neurological and ophthalmological manifestations (spastic paraplegia, cerebellar ataxia and chorioretinitis) to a very mild phenotype. Neuroendocrine profile showed apulsatile and unresponsive LH to bolus and repeated GnRH exposure. Molecular analyses showed a variable degree of loss of activity of NTE function according to various mutations. A phenotype-genotype correlation was observed, with a low impact NTE disruption seen in patients with the mildest phenotype.
Conclusion: PNPLA6 mutations are associated with a more diverse phenotype than that previously known. PNPLA6 mutations cause a pituitary deficiency at the level of gonadotropes. Following our results, we recommend to include the sequencing of PNPLA6 gene in all patients with CHH.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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