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

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Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. / Cabezas, Oscar Rubio; Flanagan, Sarah E.; Stanescu, Horia; García-Martínez, Elena; Caswell, Richard; Lango-Allen, Hana; Antón-Gamero, Montserrat; Argente, Jesús; Bussell, Anna Marie; Brandli, Andre; Cheshire, Chris; Crowne, Elizabeth; Dumitriu, Simona; Drynda, Robert; Hamilton-Shield, Julian P.; Hayes, Wesley; Hofherr, Alexis; Iancu, Daniela; Issler, Naomi; Jefferies, Craig; Jones, Peter; Johnson, Matthew; Kesselheim, Anne; Klootwijk, Enriko; Koettgen, Michael; Lewis, Wendy; Martos, José María; Mozere, Monika; Norman, Jill; Patel, Vaksha; Parrish, Andrew; Pérez-Cerdá, Celia; Pozo, Jesús; Rahman, Sofia A.; Sebire, Neil; Tekman, Mehmet; Turnpenny, Peter D.; Van'T Hoff, William; Viering, Daan H.H.M.; Weedon, Michael N.; Wilson, Patricia; Guay-Woodford, Lisa; Kleta, Robert; Hussain, Khalid; Ellard, Sian; Bockenhauer, Detlef.

In: Journal of the American Society of Nephrology, Vol. 28, No. 8, 01.08.2017, p. 2529-2539.

Research output: Contribution to journalArticle

Harvard

Cabezas, OR, Flanagan, SE, Stanescu, H, García-Martínez, E, Caswell, R, Lango-Allen, H, Antón-Gamero, M, Argente, J, Bussell, AM, 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 2017, 'Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2', Journal of the American Society of Nephrology, vol. 28, no. 8, pp. 2529-2539. https://doi.org/10.1681/ASN.2016121312

APA

Cabezas, O. R., Flanagan, S. E., Stanescu, H., García-Martínez, E., Caswell, R., Lango-Allen, H., ... Bockenhauer, D. (2017). Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. Journal of the American Society of Nephrology, 28(8), 2529-2539. https://doi.org/10.1681/ASN.2016121312

Vancouver

Cabezas OR, Flanagan SE, Stanescu H, García-Martínez E, Caswell R, Lango-Allen H et al. Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. Journal of the American Society of Nephrology. 2017 Aug 1;28(8):2529-2539. https://doi.org/10.1681/ASN.2016121312

Author

Cabezas, Oscar Rubio ; Flanagan, Sarah E. ; Stanescu, Horia ; García-Martínez, Elena ; Caswell, Richard ; Lango-Allen, Hana ; Antón-Gamero, Montserrat ; Argente, Jesús ; Bussell, Anna Marie ; Brandli, Andre ; Cheshire, Chris ; Crowne, Elizabeth ; Dumitriu, Simona ; Drynda, Robert ; Hamilton-Shield, Julian P. ; Hayes, Wesley ; Hofherr, Alexis ; Iancu, Daniela ; Issler, Naomi ; Jefferies, Craig ; Jones, Peter ; Johnson, Matthew ; Kesselheim, Anne ; Klootwijk, Enriko ; Koettgen, Michael ; Lewis, Wendy ; Martos, José María ; Mozere, Monika ; Norman, Jill ; Patel, Vaksha ; Parrish, Andrew ; Pérez-Cerdá, Celia ; Pozo, Jesús ; Rahman, Sofia A. ; Sebire, Neil ; Tekman, Mehmet ; Turnpenny, Peter D. ; Van'T Hoff, William ; Viering, Daan H.H.M. ; Weedon, Michael N. ; Wilson, Patricia ; Guay-Woodford, Lisa ; Kleta, Robert ; Hussain, Khalid ; Ellard, Sian ; Bockenhauer, Detlef. / Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. In: Journal of the American Society of Nephrology. 2017 ; Vol. 28, No. 8. pp. 2529-2539.

Bibtex

@article{a264c3d3c4074d09b3660a091347a46f,
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 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 = "polycystic kidney disease, hyperinsulinemic hypoglycemia, glycosylation, promoter, PMM2, ZNF143",
author = "Cabezas, {Oscar Rubio} and Flanagan, {Sarah E.} and Horia Stanescu and Elena Garc{\'i}a-Mart{\'i}nez and Richard Caswell and Hana Lango-Allen and Montserrat Ant{\'o}n-Gamero and Jes{\'u}s Argente and Bussell, {Anna Marie} and Andre Brandli and Chris Cheshire and Elizabeth Crowne and Simona Dumitriu and Robert Drynda and Hamilton-Shield, {Julian P.} and Wesley Hayes and Alexis Hofherr and Daniela Iancu and Naomi Issler and Craig Jefferies and Peter Jones and Matthew Johnson and Anne Kesselheim and Enriko Klootwijk and Michael Koettgen and Wendy Lewis and Martos, {Jos{\'e} Mar{\'i}a} and Monika Mozere and Jill Norman and Vaksha Patel and Andrew Parrish and Celia P{\'e}rez-Cerd{\'a} and Jes{\'u}s Pozo and Rahman, {Sofia A.} and Neil Sebire and Mehmet Tekman and Turnpenny, {Peter D.} and {Van'T Hoff}, William and Viering, {Daan H.H.M.} and Weedon, {Michael N.} and Patricia Wilson and Lisa Guay-Woodford and Robert Kleta and Khalid Hussain and Sian Ellard and Detlef Bockenhauer",
year = "2017",
month = "8",
day = "1",
doi = "10.1681/ASN.2016121312",
language = "English",
volume = "28",
pages = "2529--2539",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2

AU - Cabezas, Oscar Rubio

AU - Flanagan, Sarah E.

AU - Stanescu, Horia

AU - García-Martínez, Elena

AU - Caswell, Richard

AU - Lango-Allen, Hana

AU - Antón-Gamero, Montserrat

AU - Argente, Jesús

AU - Bussell, Anna Marie

AU - Brandli, Andre

AU - Cheshire, Chris

AU - Crowne, Elizabeth

AU - Dumitriu, Simona

AU - Drynda, Robert

AU - Hamilton-Shield, Julian P.

AU - Hayes, Wesley

AU - Hofherr, Alexis

AU - Iancu, Daniela

AU - Issler, Naomi

AU - Jefferies, Craig

AU - Jones, Peter

AU - Johnson, Matthew

AU - Kesselheim, Anne

AU - Klootwijk, Enriko

AU - Koettgen, Michael

AU - Lewis, Wendy

AU - Martos, José María

AU - Mozere, Monika

AU - Norman, Jill

AU - Patel, Vaksha

AU - Parrish, Andrew

AU - Pérez-Cerdá, Celia

AU - Pozo, Jesús

AU - Rahman, Sofia A.

AU - Sebire, Neil

AU - Tekman, Mehmet

AU - Turnpenny, Peter D.

AU - Van'T Hoff, William

AU - Viering, Daan H.H.M.

AU - Weedon, Michael N.

AU - Wilson, Patricia

AU - Guay-Woodford, Lisa

AU - Kleta, Robert

AU - Hussain, Khalid

AU - Ellard, Sian

AU - Bockenhauer, Detlef

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - polycystic kidney disease

KW - hyperinsulinemic hypoglycemia

KW - glycosylation

KW - promoter

KW - PMM2

KW - ZNF143

UR - http://www.scopus.com/inward/record.url?scp=85020588727&partnerID=8YFLogxK

U2 - 10.1681/ASN.2016121312

DO - 10.1681/ASN.2016121312

M3 - Article

C2 - 28373276

AN - SCOPUS:85020588727

VL - 28

SP - 2529

EP - 2539

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 8

ER -