title: 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 orin transwithPMM2coding mutations.PMM2encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreaticβcells altered insulin secretion. Recessive coding mutations inPMM2cause 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,thePMM2promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143.In silicoanalysis suggested an important role of ZNF143 for the formation of a chromatin loop includingPMM2We propose that thePMM2promoter 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 andPMM2pleiotropy.
authors.affiliation: Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
authors.forename: Oscar Rubio
authors.initials: OR
authors.lastname: Cabezas
authors.affiliation: University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Horia
authors.initials: H
authors.lastname: Stanescu
authors.affiliation: Pediatric Nephrology, Hospital Universitario Reina Sofía, Córdoba, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martínez
authors.affiliation: University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Caswell
authors.affiliation: University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom.
authors.forename: Hana
authors.initials: H
authors.lastname: Lango-Allen
authors.affiliation: Pediatric Nephrology, Hospital Universitario Reina Sofía, Córdoba, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Antón-Gamero
authors.affiliation: 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.
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.affiliation: University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom.
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Bussell
authors.affiliation: Walter-Brendel-Center of Experimental Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Brandli
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Cheshire
authors.affiliation: University of Bristol and Bristol Royal Hospital for Children, Bristol, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Crowne
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Simona
authors.initials: S
authors.lastname: Dumitriu
authors.affiliation: Diabetes Research Group, King's College, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Drynda
authors.affiliation: University of Bristol and Bristol Royal Hospital for Children, Bristol, United Kingdom.
authors.forename: Julian P
authors.initials: JP
authors.lastname: Hamilton-Shield
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
authors.forename: Wesley
authors.initials: W
authors.lastname: Hayes
authors.affiliation: Renal Division, Department of Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Hofherr
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Daniela
authors.initials: D
authors.lastname: Iancu
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Naomi
authors.initials: N
authors.lastname: Issler
authors.affiliation: Starship Children's Hospital, Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Craig
authors.initials: C
authors.lastname: Jefferies
authors.affiliation: Diabetes Research Group, King's College, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Jones
authors.affiliation: University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Johnson
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Kesselheim
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Enriko
authors.initials: E
authors.lastname: Klootwijk
authors.affiliation: Renal Division, Department of Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Koettgen
authors.affiliation: East of Scotland Genetic Service, Dundee, United Kingdom.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lewis
authors.affiliation: Pediatric Endocrinology, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Martos
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Monika
authors.initials: M
authors.lastname: Mozere
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Jill
authors.initials: J
authors.lastname: Norman
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Vaksha
authors.initials: V
authors.lastname: Patel
authors.affiliation: University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Parrish
authors.affiliation: 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.
authors.forename: Celia
authors.initials: C
authors.lastname: Pérez-Cerdá
authors.affiliation: Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Pozo
authors.affiliation: University College London Institute of Child Health, London, United Kingdom.
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Rahman
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.|University College London Institute of Child Health, London, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Sebire
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Tekman
authors.affiliation: Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Turnpenny
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
authors.forename: William Van't
authors.initials: WV
authors.lastname: Hoff
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Daan H H M
authors.initials: DHHM
authors.lastname: Viering
authors.affiliation: University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: University College London Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Patricia
authors.initials: P
authors.lastname: Wilson
authors.affiliation: Children's National Health System, Washington, DC; and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Guay-Woodford
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.|Department of Pediatric Medicine, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
authors.affiliation: University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: 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.
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
mesh_terms: D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000150:complications* / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D017875:Phosphotransferases (Phosphomutases) / Q000235:genetics*; D007690:Polycystic Kidney Diseases / Q000150:complications* / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D017875:Phosphotransferases (Phosphomutases); C519582:phosphomannomutase 2, human
keywords: PMM2; ZNF143; glycosylation; hyperinsulinemic hypoglycemia; polycystic kidney disease; promoter