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

Autor:	Cabezas OR; Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain., Flanagan SE; University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom., Stanescu H; University College London Centre for Nephrology, University College London, London, United Kingdom., García-Martínez E; Pediatric Nephrology, Hospital Universitario Reina Sofía, Córdoba, Spain., Caswell R; University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom., Lango-Allen H; University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom., Antón-Gamero M; Pediatric Nephrology, Hospital Universitario Reina Sofía, Córdoba, Spain., Argente J; Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.; Instituto de Investigación La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.; 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., Bussell AM; University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom., Brandli A; Walter-Brendel-Center of Experimental Medicine, Ludwig-Maximilians-University Munich, Munich, Germany., Cheshire C; University College London Centre for Nephrology, University College London, London, United Kingdom., Crowne E; University of Bristol and Bristol Royal Hospital for Children, Bristol, United Kingdom., Dumitriu S; University College London Centre for Nephrology, University College London, London, United Kingdom., Drynda R; Diabetes Research Group, King's College, London, United Kingdom., Hamilton-Shield JP; University of Bristol and Bristol Royal Hospital for Children, Bristol, United Kingdom., Hayes W; Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom., Hofherr A; Renal Division, Department of Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Iancu D; University College London Centre for Nephrology, University College London, London, United Kingdom., Issler N; University College London Centre for Nephrology, University College London, London, United Kingdom., Jefferies C; Starship Children's Hospital, Liggins Institute, University of Auckland, Auckland, New Zealand., Jones P; Diabetes Research Group, King's College, London, United Kingdom., Johnson M; University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom., Kesselheim A; University College London Centre for Nephrology, University College London, London, United Kingdom., Klootwijk E; University College London Centre for Nephrology, University College London, London, United Kingdom., Koettgen M; Renal Division, Department of Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Lewis W; East of Scotland Genetic Service, Dundee, United Kingdom., Martos JM; Pediatric Endocrinology, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain., Mozere M; University College London Centre for Nephrology, University College London, London, United Kingdom., Norman J; University College London Centre for Nephrology, University College London, London, United Kingdom., Patel V; University College London Centre for Nephrology, University College London, London, United Kingdom., Parrish A; University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom., Pérez-Cerdá C; 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., Pozo J; Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain., Rahman SA; University College London Institute of Child Health, London, United Kingdom., Sebire N; Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.; University College London Institute of Child Health, London, United Kingdom., Tekman M; University College London Centre for Nephrology, University College London, London, United Kingdom., Turnpenny PD; Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom., Hoff WV; Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom., Viering DHHM; University College London Centre for Nephrology, University College London, London, United Kingdom., Weedon MN; University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom., Wilson P; University College London Centre for Nephrology, University College London, London, United Kingdom., Guay-Woodford L; Children's National Health System, Washington, DC; and., Kleta R; University College London Centre for Nephrology, University College London, London, United Kingdom.; Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.; University College London Institute of Child Health, London, United Kingdom., Hussain K; Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.; Department of Pediatric Medicine, Sidra Medical and Research Center, Doha, Qatar., Ellard S; University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom., Bockenhauer D; University College London Centre for Nephrology, University College London, London, United Kingdom.; Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.; University College London Institute of Child Health, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2017 Aug; Vol. 28 (8), pp. 2529-2539. Date of Electronic Publication: 2017 Apr 03.
DOI:	10.1681/ASN.2016121312
Abstrakt:	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.)
Databáze:	MEDLINE
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