RT Journal Article
T1 Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2.
A1 Cabezas, Oscar Rubio
A1 Flanagan, Sarah E
A1 Stanescu, Horia
A1 García-Martínez, Elena
A1 Caswell, Richard
A1 Lango-Allen, Hana
A1 Antón-Gamero, Montserrat
A1 Argente, Jesús
A1 Bussell, Anna-Marie
A1 Brandli, Andre
A1 Cheshire, Chris
A1 Crowne, Elizabeth
A1 Dumitriu, Simona
A1 Drynda, Robert
A1 Hamilton-Shield, Julian P
A1 Hayes, Wesley
A1 Hofherr, Alexis
A1 Iancu, Daniela
A1 Issler, Naomi
A1 Jefferies, Craig
A1 Jones, Peter
A1 Johnson, Matthew
A1 Kesselheim, Anne
A1 Klootwijk, Enriko
A1 Koettgen, Michael
A1 Lewis, Wendy
A1 Martos, José María
A1 Mozere, Monika
A1 Norman, Jill
A1 Patel, Vaksha
A1 Parrish, Andrew
A1 Pérez-Cerdá, Celia
A1 Pozo, Jesús
A1 Rahman, Sofia A
A1 Sebire, Neil
A1 Tekman, Mehmet
A1 Turnpenny, Peter D
A1 Hoff, William Van't
A1 Viering, Daan H H M
A1 Weedon, Michael N
A1 Wilson, Patricia
A1 Guay-Woodford, Lisa
A1 Kleta, Robert
A1 Hussain, Khalid
A1 Ellard, Sian
A1 Bockenhauer, Detlef
K1 PMM2
K1 ZNF143
K1 glycosylation
K1 hyperinsulinemic hypoglycemia
K1 polycystic kidney disease
K1 promoter
AB 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.
YR 2017
FD 2017-04-03
LK http://hdl.handle.net/10668/11047
UL http://hdl.handle.net/10668/11047
LA en
DS RISalud
RD Apr 17, 2025