Browsing by Subject "Prader-Willi Syndrome"

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    Breakage in the SNRPN locus in a balanced 46,XY,t(15;19) Prader-Willi syndrome patient
    (Oxford Academic, 1996-04) Sun, Yongming; Nicholls, Robert D.; Butler, Merlin G.; Saitoh, Shinji; Hainline, Bryan E.; Palmer, Catherine G.; Medical and Molecular Genetics, School of Medicine
    A patient with Prader-Willi syndrome (PWS) was found to carry a de novo balanced reciprocal translocation, t(15;19)(q12;q13.41), which disrupted the small nuclear ribonucleoprotein N (SNRPN) locus. The translocation chromosome 15 was found to be paternal in origin. Uniparental disomy and abnormal DNA methylation were ruled out. The translocation breakpoint was found to have occurred between exon 0 (second exon) and 1 (third exon) of the SNRPN locus outside of the SmN open reading frame (ORF), which is intact. The transcriptional activities of ZNF127, IPW, PAR-1, and PAR-5 were detected with RT-PCR from fibroblasts of the patient, suggesting that these genes may not play a significant role in the PWS phenotype in this patient. Transcription from the first two exons and last seven exons of the SNRPN gene was also detected with RT-PCR; however, the complete mRNA (10 exons) was not detected. Thus, the PWS phenotype in the patient is likely to be the result of disruption of the SNRPN locus.
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    Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones
    (Public Library of Science, 2023-04-17) Koppes, Erik A.; Johnson, Marie A.; Moresco, James J.; Luppi, Patrizia; Lewis, Dale W.; Stolz, Donna B.; Diedrich, Jolene K.; Yates, John R., III; Wek, Ronald C.; Watkins, Simon C.; Gollin, Susanne M.; Park, Hyun Jung; Drain, Peter; Nicholls, Robert D.; Biochemistry and Molecular Biology, School of Medicine
    Prader-Willi syndrome (PWS) is a multisystem disorder with neurobehavioral, metabolic, and hormonal phenotypes, caused by loss of expression of a paternally-expressed imprinted gene cluster. Prior evidence from a PWS mouse model identified abnormal pancreatic islet development with retention of aged insulin and deficient insulin secretion. To determine the collective roles of PWS genes in β-cell biology, we used genome-editing to generate isogenic, clonal INS-1 insulinoma lines having 3.16 Mb deletions of the silent, maternal- (control) and active, paternal-allele (PWS). PWS β-cells demonstrated a significant cell autonomous reduction in basal and glucose-stimulated insulin secretion. Further, proteomic analyses revealed reduced levels of cellular and secreted hormones, including all insulin peptides and amylin, concomitant with reduction of at least ten endoplasmic reticulum (ER) chaperones, including GRP78 and GRP94. Critically, differentially expressed genes identified by whole transcriptome studies included reductions in levels of mRNAs encoding these secreted peptides and the group of ER chaperones. In contrast to the dosage compensation previously seen for ER chaperones in Grp78 or Grp94 gene knockouts or knockdown, compensation is precluded by the stress-independent deficiency of ER chaperones in PWS β-cells. Consistent with reduced ER chaperones levels, PWS INS-1 β-cells are more sensitive to ER stress, leading to earlier activation of all three arms of the unfolded protein response. Combined, the findings suggest that a chronic shortage of ER chaperones in PWS β-cells leads to a deficiency of protein folding and/or delay in ER transit of insulin and other cargo. In summary, our results illuminate the pathophysiological basis of pancreatic β-cell hormone deficits in PWS, with evolutionary implications for the multigenic PWS-domain, and indicate that PWS-imprinted genes coordinate concerted regulation of ER chaperone biosynthesis and β-cell secretory pathway function.
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    Prader-Willi syndrome: are there population differences?
    (Wiley, 1982-11) Butler, Merlin G.; Weaver, David D.; Meaney, F. John; Medical and Molecular Genetics, School of Medicine
    A 15 1/2-year-old black female with features consistent with the Prader-Willi syndrome is reported. This is the second case report of a black individual and the first case of a black female with the Prader-Willi syndrome. There is an apparent paucity of blacks reported with this condition. Whether this difference is a true difference or represents under-reporting is not known. We urge reporting of individuals representing other racial groups with this disorder and suggest population studies to determine the incidence as well as the true population difference in the Prader-Willi syndrome.