Hormonal Imbalances in Prader–Willi and Schaaf–Yang Syndromes Imply the Evolution of Specific Regulation of Hypothalamic Neuroendocrine Function in Mammals

Abstract

The hypothalamus regulates fundamental aspects of physiological homeostasis and behavior, including stress response, reproduction, growth, sleep, and feeding, several of which are affected in patients with Prader–Willi (PWS) and Schaaf–Yang syndrome (SYS). PWS is caused by paternal deletion, maternal uniparental disomy, or imprinting defects that lead to loss of expression of a maternally imprinted region of chromosome 15 encompassing non-coding RNAs and five protein-coding genes; SYS patients have a mutation in one of them, MAGEL2. Throughout life, PWS and SYS patients suffer from musculoskeletal deficiencies, intellectual disabilities, and hormonal abnormalities, which lead to compulsive behaviors like hyperphagia and temper outbursts. Management of PWS and SYS is mostly symptomatic and cures for these debilitating disorders do not exist, highlighting a clear, unmet medical need. Research over several decades into the molecular and cellular roles of PWS genes has uncovered that several impinge on the neuroendocrine system. In this review, we will discuss the expression and molecular functions of PWS genes, connecting them with hormonal imbalances in patients and animal models. Besides the observed hormonal imbalances, we will describe the recent findings about how the loss of individual genes, particularly MAGEL2, affects the molecular mechanisms of hormone secretion. These results suggest that MAGEL2 evolved as a mammalian-specific regulator of hypothalamic neuroendocrine function.

Cell-specific secretory granule sorting mechanisms: the role of MAGEL2 and retromer in hypothalamic regulated secretion

“…Given that the hypothalamus plays a key role in regulating many physiological processes, perturbations in the regulated secretion pathway lead to improper hypothalamic development and function that phenotypically manifests in syndromes, such as PWS and Schaaf-Yang syndrome (SYS) ( Hoyos Sanchez et al, 2023 ). PWS is a complex neurogenetic disorder caused by paternal loss of the maternally imprinted 15q11-q13 chromosomal region (called the Prader-Willi region) that contains small nucleolar RNA genes and six protein-coding genes ( MKRN3 , NDN , NPAP1 , SNURF-SNRPN , and MAGEL2 ) ( Butler et al, 2019 ; Alves and Franco, 2020 ).…”

“…While the loss of MAGEL2 affects regulated secretion in the hypothalamus ( Figure 6B ), loss of the other Prader-Willi region genes also impacts the clinical presentation of PWS ( Cassidy and Driscoll, 2009 ; Fon Tacer and Potts, 2017 ; Chen et al, 2020 ). Currently, PWS and SYS have no cure or effective therapy, and treatment focuses on managing the symptoms that arise from perturbations in the regulated secretion pathway and the dysregulation of crucial hypothalamic hormones ( Alves and Franco, 2020 ; Hoyos Sanchez et al, 2023 ). Given that PWS is relatively common and affects 1 in 15,000 children, there is a pressing need to find better treatment options ( Cassidy and Driscoll, 2009 ).…”

“…Through facilitating the activation of WASH, MAGEL2 functions as a tissue-specific regulator of ARP2/3 activation in the hypothalamus ( Hao et al, 2013 ; Hao et al, 2015 ). The loss of MAGEL2 expression causes deficits in SG abundance and bioactive neuropeptide production, impacting hypothalamic neuroendocrine function and contributing to the clinical presentation of PWS ( Figure 6B ) ( Chen et al, 2020 ; Hoyos Sanchez et al, 2023 ). In particular, reduced levels of the neuropeptides vasopressin, galanin, oxytocin, proenkephalin, somatostatin, and thyrotropin-releasing hormone and the SG components involved in their processing and release (i.e., CHGB, secretogranin II and III, PC1/3, PC2, and CPE) have been discovered in PWS mouse models and patient-derived neuronal cell models ( Chen et al, 2020 ; Hoyos Sanchez et al, 2023 ).…”