Congenital hypogonadotropic hypogonadism by PNPLA6 mutations: identification of a wide phenotypic spectrum and functional correlations with the NTE <em>in vitro</em> activity

Luigi Maione; Jerome Bouligand; Antoine Rousseau; Salome Prevost; Lydie Naule; Sylvie Salenave; Philippe Chanson; Ursula Kaiser; Jacques young

doi:10.1530/endoabs.99.P358

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Endocrine Abstracts (2024) 99 P358 | DOI: 10.1530/endoabs.99.P358

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

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Author affiliations

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.