Polycystic kidney disease with hyperinsulinemic hypoglycemia caused by a promoter mutation in phosphomannomutase 2

Oscar Rubio Cabezas, Sarah E. Flanagan, Horia Stanescu, Elena García-Martínez, Richard Caswell, Hana Lango-Allen, Montserrat Antón-Gamero, Jesús Argente, Anna Marie Bussell, Andre Brandli, Chris Cheshire, Elizabeth Crowne, Simona Dumitriu, Robert Drynda, Julian P. Hamilton-Shield, Wesley Hayes, Alexis Hofherr, Daniela Iancu, Naomi Issler, Craig JefferiesPeter Jones, Matthew Johnson, Anne Kesselheim, Enriko Klootwijk, Michael Koettgen, Wendy Lewis, José María Martos, Monika Mozere, Jill Norman, Vaksha Patel, Andrew Parrish, Celia Pérez-Cerdá, Jesús Pozo, Sofia A. Rahman, Neil Sebire, Mehmet Tekman, Peter D. Turnpenny, William Van'T Hoff, Daan H.H.M. Viering, Michael N. Weedon, Patricia Wilson, Lisa Guay-Woodford, Robert Kleta, Khalid Hussain, Sian Ellard, Detlef Bockenhauer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2529-2539
Number of pages11
JournalJournal of the American Society of Nephrology : JASN
Issue number8
Early online date3 Apr 2017
Publication statusPublished - 1 Aug 2017


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