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


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 ? 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.

SUBMITTER: Cabezas OR 

PROVIDER: S-EPMC5533241 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

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

Journal of the American Society of Nephrology : JASN 20170403 8


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 mutation  ...[more]

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