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J Am Soc Nephrol. 2017 Aug;28(8):2529-2539. doi: 10.1681/ASN.2016121312. Epub 2017 Apr 3.

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

Author information

1
Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
2
University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom.
3
University College London Centre for Nephrology, University College London, London, United Kingdom.
4
Pediatric Nephrology, Hospital Universitario Reina Sofía, Córdoba, Spain.
5
Instituto de Investigación La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
6
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
7
Madrid Institute for Advanced Studies on Food, Comité de Ética de la Investigación de la Universidad Autónoma de Madrid, and Centro Superior de Investigaciones Científicas, Carretera de Cantoblanco 8.28049, Madrid, Spain.
8
Walter-Brendel-Center of Experimental Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
9
University of Bristol and Bristol Royal Hospital for Children, Bristol, United Kingdom.
10
Diabetes Research Group, King's College, London, United Kingdom.
11
Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
12
Renal Division, Department of Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
13
Starship Children's Hospital, Liggins Institute, University of Auckland, Auckland, New Zealand.
14
East of Scotland Genetic Service, Dundee, United Kingdom.
15
Pediatric Endocrinology, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
16
Centro de Diagnóstico de Enfermedades Moleculares, Universidad Autónoma de Madrid, Center for Biomedical Research in Rare diseases, Instituto de Investigacion Hospital Universitario La Paz, Madrid, Spain.
17
University College London Institute of Child Health, London, United Kingdom.
18
Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.
19
Children's National Health System, Washington, DC; and.
20
Department of Pediatric Medicine, Sidra Medical and Research Center, Doha, Qatar.

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.

KEYWORDS:

PMM2; ZNF143; glycosylation; hyperinsulinemic hypoglycemia; polycystic kidney disease; promoter

PMID:
28373276
PMCID:
PMC5533241
DOI:
10.1681/ASN.2016121312
[Indexed for MEDLINE]
Free PMC Article

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