title: Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome.
abstract: Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Burnett
authors.forename: Charles A
authors.initials: CA
authors.lastname: LeDuc
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Sulsona
authors.forename: Daniel
authors.initials: D
authors.lastname: Paull
authors.forename: Richard
authors.initials: R
authors.lastname: Rausch
authors.forename: Sanaa
authors.initials: S
authors.lastname: Eddiry
authors.forename: Jayne F Martin
authors.initials: JF
authors.lastname: Carli
authors.forename: Michael V
authors.initials: MV
authors.lastname: Morabito
authors.forename: Alicja A
authors.initials: AA
authors.lastname: Skowronski
authors.forename: Gabriela
authors.initials: G
authors.lastname: Hubner
authors.forename: Matthew
authors.initials: M
authors.lastname: Zimmer
authors.forename: Liheng
authors.initials: L
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Day
authors.forename: Brynn
authors.initials: B
authors.lastname: Levy
authors.forename: Ilene
authors.initials: I
authors.lastname: Fennoy
authors.forename: Beatrice
authors.initials: B
authors.lastname: Dubern
authors.forename: Christine
authors.initials: C
authors.lastname: Poitou
authors.forename: Karine
authors.initials: K
authors.lastname: Clement
authors.forename: Merlin G
authors.initials: MG
authors.lastname: Butler
authors.forename: Michael
authors.initials: M
authors.lastname: Rosenbaum
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Salles
authors.forename: Maithe
authors.initials: M
authors.lastname: Tauber
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Driscoll
authors.forename: Dieter
authors.initials: D
authors.lastname: Egli
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006963:Hyperphagia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007006:Hypogonadism / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011218:Prader-Willi Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism*; D045664:Proprotein Convertase 1 / Q000172:deficiency*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D020537:RNA, Small Nucleolar / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D013007:Growth Hormone-Releasing Hormone; D011384:Proinsulin; D045664:Proprotein Convertase 1; D011498:Protein Precursors; D020537:RNA, Small Nucleolar; C484104:Nhlh2 protein, mouse; C000601579:SNORD116 RNA, human; C000609194:SNORD116 RNA, mouse; C062302:pro-growth hormone releasing hormone, mouse; C076747:NHLH2 protein, human; C587576:PCSK1 protein, human; C473656:Pcsk1 protein, mouse