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Cabezas, Oscar Rubio; Flanagan, Sarah E.; Stanescu, Horia; García-Martínez, Elena; Caswell, Richard; Lango-Allen, Hana; Antón-Gamero, Montserrat; Argente, Jesús; Bussell, Anna-Marie; Brandli, Andre; Cheshire, Chris; Crowne, Elizabeth; Dumitriu, Simona; Drynda, Robert; Hamilton-Shield, Julian P; Hayes, Wesley; Hofherr, Alexis; Iancu, Daniela; Issler, Naomi; Jefferies, Craig; Jones, Peter; Johnson, Matthew; Kesselheim, Anne; Klootwijk, Enriko; [...]

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2

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  • Media type: E-Article
  • Title: Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2
  • Contributor: Cabezas, Oscar Rubio; Flanagan, Sarah E.; Stanescu, Horia; García-Martínez, Elena; Caswell, Richard; Lango-Allen, Hana; Antón-Gamero, Montserrat; Argente, Jesús; Bussell, Anna-Marie; Brandli, Andre; Cheshire, Chris; Crowne, Elizabeth; Dumitriu, Simona; Drynda, Robert; Hamilton-Shield, Julian P; Hayes, Wesley; Hofherr, Alexis; Iancu, Daniela; Issler, Naomi; Jefferies, Craig; Jones, Peter; Johnson, Matthew; Kesselheim, Anne; Klootwijk, Enriko; [...]
  • imprint: Ovid Technologies (Wolters Kluwer Health), 2017
  • Published in: Journal of the American Society of Nephrology
  • Language: English
  • DOI: 10.1681/asn.2016121312
  • ISSN: 1046-6673; 1533-3450
  • Keywords: Nephrology ; General Medicine
  • Origination:
  • Footnote:
  • Description: <jats:p>Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G&gt;T) in the phosphomannomutase 2 gene (<jats:italic toggle="yes">PMM2</jats:italic>), either homozygous or <jats:italic toggle="yes">in trans</jats:italic> with <jats:italic toggle="yes">PMM2</jats:italic> coding mutations. <jats:italic toggle="yes">PMM2</jats:italic> encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic <jats:italic toggle="yes">β</jats:italic> cells altered insulin secretion. Recessive coding mutations in <jats:italic toggle="yes">PMM2</jats:italic> cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. <jats:italic toggle="yes">In vitro,</jats:italic> the <jats:italic toggle="yes">PMM2</jats:italic> promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. <jats:italic toggle="yes">In silico</jats:italic> analysis suggested an important role of ZNF143 for the formation of a chromatin loop including <jats:italic toggle="yes">PMM2</jats:italic>. We propose that the <jats:italic toggle="yes">PMM2</jats:italic> promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and <jats:italic toggle="yes">PMM2</jats:italic> pleiotropy.</jats:p>
  • Access State: Open Access