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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620332
Title:
Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2.
Authors:
Cabezas, O. R.; Flanagan, S. E.; Stanescu, H.; García-Martínez, E.; Caswell, R.; Lango-Allen, H.; Antón-Gamero, M.; Argente, J.; Bussell, A-M; Brandli, A.; Cheshire, C.; Crowne, E.; Dumitriu, S.; Drynda, R.; Hamilton-Shield, J. P.; Hayes, W.; Hofherr, A.; Iancu, D.; Issler, N.; Jefferies, C.; Jones, P.; Johnson, M. B.; Kesselheim, A.; Klootwijk, E.; Koettgen, M.; Lewis, W.; Martos, J. M.; Mozere, M.; Norman, J.; Patel, V.; Parrish, A.; Pérez-Cerdá, C.; Pozo, J.; Rahman, S.A.; Sebire, N.; Tekman, M.; Turnpenny, Peter D.; Hoff, W. V.; Viering, D. H H M; Weedon, M. N.; Wilson, P.; Guay-Woodford, L.; Kleta, R.; Hussain, K.; Ellard, Sian ( 0000-0002-7620-5526 ) ; Bockenhauer, D.
Abstract:
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>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic β cells altered insulin secretion. Recessive coding mutations in PMM2 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. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 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 PMM2 pleiotropy.
Citation:
Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. 2017 Aug;28(8):2529-2539 J. Am. Soc. Nephrol.
Publisher:
American Society of Nephrology
Journal:
Journal of the American Society of Nephrology : JASN
Issue Date:
3-Apr-2017
URI:
http://hdl.handle.net/11287/620332
DOI:
10.1681/ASN.2016121312
PubMed ID:
28373276
Additional Links:
http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=28373276
Type:
Journal Article
Language:
en
ISSN:
1533-3450
Appears in Collections:
Clinical Genetics (Peninsula Genetics); Molecular Genetics; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorCabezas, O. R.en
dc.contributor.authorFlanagan, S. E.en
dc.contributor.authorStanescu, H.en
dc.contributor.authorGarcía-Martínez, E.en
dc.contributor.authorCaswell, R.en
dc.contributor.authorLango-Allen, H.en
dc.contributor.authorAntón-Gamero, M.en
dc.contributor.authorArgente, J.en
dc.contributor.authorBussell, A-Men
dc.contributor.authorBrandli, A.en
dc.contributor.authorCheshire, C.en
dc.contributor.authorCrowne, E.en
dc.contributor.authorDumitriu, S.en
dc.contributor.authorDrynda, R.en
dc.contributor.authorHamilton-Shield, J. P.en
dc.contributor.authorHayes, W.en
dc.contributor.authorHofherr, A.en
dc.contributor.authorIancu, D.en
dc.contributor.authorIssler, N.en
dc.contributor.authorJefferies, C.en
dc.contributor.authorJones, P.en
dc.contributor.authorJohnson, M. B.en
dc.contributor.authorKesselheim, A.en
dc.contributor.authorKlootwijk, E.en
dc.contributor.authorKoettgen, M.en
dc.contributor.authorLewis, W.en
dc.contributor.authorMartos, J. M.en
dc.contributor.authorMozere, M.en
dc.contributor.authorNorman, J.en
dc.contributor.authorPatel, V.en
dc.contributor.authorParrish, A.en
dc.contributor.authorPérez-Cerdá, C.en
dc.contributor.authorPozo, J.en
dc.contributor.authorRahman, S.A.en
dc.contributor.authorSebire, N.en
dc.contributor.authorTekman, M.en
dc.contributor.authorTurnpenny, Peter D.en
dc.contributor.authorHoff, W. V.en
dc.contributor.authorViering, D. H H Men
dc.contributor.authorWeedon, M. N.en
dc.contributor.authorWilson, P.en
dc.contributor.authorGuay-Woodford, L.en
dc.contributor.authorKleta, R.en
dc.contributor.authorHussain, K.en
dc.contributor.authorEllard, Sianen
dc.contributor.authorBockenhauer, D.en
dc.date.accessioned2017-05-17T14:20:28Z-
dc.date.available2017-05-17T14:20:28Z-
dc.date.issued2017-04-03-
dc.identifier.citationPolycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. 2017 Aug;28(8):2529-2539 J. Am. Soc. Nephrol.en
dc.identifier.issn1533-3450-
dc.identifier.pmid28373276-
dc.identifier.doi10.1681/ASN.2016121312-
dc.identifier.urihttp://hdl.handle.net/11287/620332-
dc.description.abstractHyperinsulinemic 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>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic β cells altered insulin secretion. Recessive coding mutations in PMM2 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. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 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 PMM2 pleiotropy.en
dc.language.isoenen
dc.publisherAmerican Society of Nephrologyen
dc.relation.urlhttp://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=28373276en
dc.rightsArchived with thanks to Journal of the American Society of Nephrology : JASNen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titlePolycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2.en
dc.typeJournal Articleen
dc.identifier.journalJournal of the American Society of Nephrology : JASNen
dc.type.versionIn press (epub ahead of print)en

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