Imperial College London
Alternate

DrAnishaWijeyesekera

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Honorary Lecturer
 
 
 
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Contact

 

anisha.wijeyesekera04 Website

 
 
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Location

 

380ASir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Klootwijk:2014:10.1056/NEJMoa1307581,
author = {Klootwijk, ED and Reichold, M and Helip-Wooley, A and Tolaymat, A and Broeker, C and Robinette, SL and Reinders, J and Peindl, D and Renner, K and Eberhart, K and Assmann, N and Oefner, PJ and Dettmer, K and Sterner, C and Schroeder, J and Zorger, N and Witzgall, R and Reinhold, SW and Stanescu, HC and Bockenhauer, D and Jaureguiberry, G and Courtneidge, H and Hall, AM and Wijeyesekera, AD and Holmes, E and Nicholson, JK and O'Brien, K and Bernardini, I and Krasnewich, DM and Arcos-Burgos, M and Izumi, Y and Nonoguchi, H and Jia, Y and Reddy, JK and Ilyas, M and Unwin, RJ and Gahl, WA and Warth, R and Kleta, R},
doi = {10.1056/NEJMoa1307581},
journal = {New England Journal of Medicine},
pages = {129--138},
title = {Mistargeting of peroxisomal EHHADH and inherited renal fanconi's syndrome},
url = {http://dx.doi.org/10.1056/NEJMoa1307581},
volume = {370},
year = {2014}
}
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TY  - JOUR
AB  - BACKGROUNDIn renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to renal losses of water, electrolytes, and low-molecular-weight nutrients. For most types of isolated Fanconi's syndrome, the genetic cause and underlying defect remain unknown.METHODSWe clinically and genetically characterized members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome. We performed genomewide linkage analysis, gene sequencing, biochemical and cell-biologic investigations of renal proximal tubular cells, studies in knockout mice, and functional evaluations of mitochondria. Urine was studied with the use of proton nuclear magnetic resonance (1H-NMR) spectroscopy.RESULTSWe linked the phenotype of this family's Fanconi's syndrome to a single locus on chromosome 3q27, where a heterozygous missense mutation in EHHADH segregated with the disease. The p.E3K mutation created a new mitochondrial targeting motif in the N-terminal portion of EHHADH, an enzyme that is involved in peroxisomal oxidation of fatty acids and is expressed in the proximal tubule. Immunocytofluorescence studies showed mistargeting of the mutant EHHADH to mitochondria. Studies of proximal tubular cells revealed impaired mitochondrial oxidative phosphorylation and defects in the transport of fluids and a glucose analogue across the epithelium. 1H-NMR spectroscopy showed elevated levels of mitochondrial metabolites in urine from affected family members. Ehhadh knockout mice showed no abnormalities in renal tubular cells, a finding that indicates a dominant negative nature of the mutation rather than haploinsufficiency.CONCLUSIONSMistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi's syndrome; this indicates a central role of mitochondria in proximal tubular function. The dominant negative effect of the mistargeted protein adds to the spectrum of monogenic mechanisms of Fanconi's syndrome. (Funded by the European Commission Sevent
AU  - Klootwijk,ED
AU  - Reichold,M
AU  - Helip-Wooley,A
AU  - Tolaymat,A
AU  - Broeker,C
AU  - Robinette,SL
AU  - Reinders,J
AU  - Peindl,D
AU  - Renner,K
AU  - Eberhart,K
AU  - Assmann,N
AU  - Oefner,PJ
AU  - Dettmer,K
AU  - Sterner,C
AU  - Schroeder,J
AU  - Zorger,N
AU  - Witzgall,R
AU  - Reinhold,SW
AU  - Stanescu,HC
AU  - Bockenhauer,D
AU  - Jaureguiberry,G
AU  - Courtneidge,H
AU  - Hall,AM
AU  - Wijeyesekera,AD
AU  - Holmes,E
AU  - Nicholson,JK
AU  - O'Brien,K
AU  - Bernardini,I
AU  - Krasnewich,DM
AU  - Arcos-Burgos,M
AU  - Izumi,Y
AU  - Nonoguchi,H
AU  - Jia,Y
AU  - Reddy,JK
AU  - Ilyas,M
AU  - Unwin,RJ
AU  - Gahl,WA
AU  - Warth,R
AU  - Kleta,R
DO  - 10.1056/NEJMoa1307581
EP  - 138
PY  - 2014///
SN  - 0028-4793
SP  - 129
TI  - Mistargeting of peroxisomal EHHADH and inherited renal fanconi's syndrome
T2  - New England Journal of Medicine
UR  - http://dx.doi.org/10.1056/NEJMoa1307581
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000336119800008&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.nejm.org/doi/10.1056/NEJMoa1307581
VL  - 370
ER  -
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