Dysfunction of the Hypothalamic-Pituitary Axis in Prader-Willi Syndrome: An emerging understanding of pertinent genetic and molecular players

Brooke Evans

Introduction. Prader-Willi Syndrome (PWS) is the leading syndromic cause of obesity.The syndrome is caused by non-expression of paternally imprinted genes on chromosome 15 (15q11.2-13) and was the first human disorder linked to genomic imprinting.2 The minimal critical deletion chromosomal domain for PWS contains a non-coding RNA SNORD116 which research shows is involved in PWS pathology.3 The classical PWS phenotype is characterized by hypotonia and poor feeding in neonates. Starting in infancy, patients present with hyperphagia, obesity, short stature, hypogonadism, and abnormal cognitive and behavioral development.  The pathophysiological basis of much of the PWS phenotype is largely attributed to hormonal imbalances (i.e., Growth hormone and thyroid stimulating hormone deficiencies) caused by disturbances in the hypothalamic-pituitary axis.4 The genetic determinants and physiological mechanisms of these endocrine abnormalities are at the fore of current PWS research.  Methods. Unidirectional RNA sequencing was conducted on induced pluripotent stem cell (iPSC) derived neurons from 4 paternal deletion PWS patients and 6 non-PWS patients to determine downregulated genes and pathway analysis was utilized to determine dysregulated pathways. 5 In other investigational studies, the effect of CRISPER knock out (KO) of the zinc-finger protein (ZNF274) containing epigenetic complex responsible for silencing the maternal chromosomal copy of the PWS was tested.Results. A two-tailed type 3 student’s t-test found a statistically significant (p<0.05) decrease in the concentration of Prohormone convertase (PC1) protein and PCKS1 (which encodes PC1) in mice with paternal SNORD116 deletion (Snord116+/-P mice) when compared to their wild-type littermates. The Snord116+/-P mice also had higher prohormone/hormone ratios than their littermates.5 CRISPER zNF274 protein KO in the PWS iPSC models resulted in a >100x increase in PWS iPSC neuronal expression of previously silent maternal alleles within the PWS minimal critical deletion region. Conclusion. Studies have demonstrated that within the PWS critical region, SNORD116 is believed to contribute to dysfunction of the hypothalamic-pituitary axis leading to decreased levels of PC1 and, in turn, abnormally low hormone levels characteristic of PWS.5 Additionally, there is a role for CRISPER technology in the knock out of a ZNFP279 complex which would rescue the epigenetically silenced maternal copy of the PWS region.6 Advances is understanding the genotypic-phenotypic associations (which genes cause which pathological processes and, in turn, which clinical manifestations) related to growth hormone deficiency and related symptomology in PWS have the potential to improve the efficacy of current treatment options and illuminate additional therapeutic options.

 

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