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Article

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

Publicated to:JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. 28 (8): 2529-2539 - 2017-01-01 28(8), DOI: 10.1681/ASN.2016121312

Authors: Cabezas OR; Flanagan SE; 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 JP; Hayes W; Hofherr A; Iancu D; Issler N; Jefferies C; Jones P; Johnson M; Kesselheim A; Klootwijk E; Koettgen M; Lewis W; Martos JM; Mozere M; Norman J; Patel V; Parrish A; Pérez-Cerdá C; Pozo J; Rahman SA; Sebire N; Tekman M; Turnpenny PD; Van'T Hoff W; Viering DHHM; Weedon MN; Wilson P; Guay-Woodford L; Kleta R; Hussain K; Ellard S; Bockenhauer D

Affiliations

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 - Author
Children's National Health System; Washington; DC; United States - Author
Clinical Genetics; Royal Devon and Exeter NHS Foundation Trust; Exeter; United Kingdom - Author
Diabetes Research Group; King's College; London; United Kingdom - Author
East of Scotland Genetic Service; Dundee; United Kingdom - Author
Great Ormond Street Hospital for Children NHS Foundation Trust; London; United Kingdom - Author
Great Ormond Street Hospital for Children NHS Foundation Trust; London; United Kingdom; Department of Pediatric Medicine; Sidra Medical and Research Center; Doha; Qatar - Author
Great Ormond Street Hospital for Children NHS Foundation Trust; London; United Kingdom; University College London Institute of Child Health; London; United Kingdom - Author
Pediatric Endocrinology; Hospital Clínico Universitario Virgen de la Arrixaca; Murcia; Spain - Author
Pediatric Endocrinology; Hospital Infantil Universitario Niño Jesús; Madrid; Spain - Author
Pediatric Endocrinology; Hospital Infantil Universitario Niño Jesús; Madrid; Spain; Instituto de Investigación la Princesa; Universidad Autónoma de Madrid; Madrid; Spain; Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y Nutricio - Author
Pediatric Nephrology; Hospital Universitario Reina Sofía3; Córdoba; Spain - Author
Renal Division; Department of Medicine; Faculty of Medicine; University of Freiburg; Freiburg; Germany - Author
Starship Children's Hospital; Liggins Institute; University of Auckland; Auckland; New Zealand - Author
University College London Centre for Nephrology; University College London; Rowland Hill Street; London; NW3 2PF; United Kingdom - Author
University College London Centre for Nephrology; University College London; Rowland Hill Street; London; NW3 2PF; United Kingdom; Great Ormond Street Hospital for Children NHS Foundation Trust; London; United Kingdom; University College London Institute o - Author
University College London Institute of Child Health; London; United Kingdom - Author
University of Bristol and Bristol Royal Hospital for Children; Bristol; United Kingdom - Author
University of Exeter Medical School; Institute of Biomedical and Clinical Science; Exeter; United Kingdom - Author
Walter-Brendel-Center of Experimental Medicine; Ludwig-Maximilians-University Munich; Munich; Germany - Author
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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. Copyright © 2017 by the American Society of Nephrology.

Keywords
ArticleChildChild, preschoolChromosome 16pClinical articleComplicationCongenital disorder of glycosylation type 1aCongenital hyperinsulinismControlled studyFemaleGene controlGene locusGene mutationGenetic analysisGenetic associationGenetic codeGeneticsGlycosylationHomozygoteHumanHumansIn vitro studyInfantInfant, newbornInsulin releaseKidney polycystic diseaseLinkage analysisLiver diseaseMaleMutaseMutationNeurologic diseaseNewbornPancreas islet beta cellPersistent hyperinsulinemic hypoglycemia of infancyPhosphomannomutasePhosphomannomutase 2Phosphomannomutase 2, humanPhosphotransferases (phosphomutases)Polycystic kidney diseasesPreschool childPriority journalPromoter regionPromoter regions, geneticProtein bindingProtein znf143Transcription factorUnclassified drug

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2017, it was in position 3/76, thus managing to position itself as a Q1 (Primer Cuartil), in the category Urology & Nephrology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations from Scopus Elsevier, it yields a value for the Field-Weighted Citation Impact from the Scopus agency: 20.68, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Field Citation Ratio (FCR) from Dimensions: 26.13 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-23, the following number of citations:

  • Scopus: 91
  • Google Scholar: 118
  • OpenCitations: 90
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-23:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 91.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 87 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 19.5.
  • The number of mentions on the social network Facebook: 2 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 19 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Germany; New Zealand; Qatar; United Kingdom; United States of America.