Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 3, 673-684, 28 February 2008
doi:10.1016/j.ajhg.2007.12.019
Article
Array-Based Gene Discovery with Three Unrelated Subjects Shows SCARB2/LIMP-2 Deficiency Causes Myoclonus Epilepsy and Glomerulosclerosis
Samuel F. Berkovic1, 2, 3, 
, 
, Leanne M. Dibbens4, 5, Alicia Oshlack6, Jeremy D. Silver6, 7, Marina Katerelos8, Danya F. Vears1, 2, Renate Lüllmann-Rauch9, Judith Blanz10, Ke Wei Zhang1, Jim Stankovich6, 11, Renate M. Kalnins3, John P. Dowling12, Eva Andermann13, Frederick Andermann13, Enrico Faldini14, Rudi D'Hooge14, Lata Vadlamudi1, 2, Richard A. Macdonell3, Bree L. Hodgson4, Marta A. Bayly4, Judy Savige1, John C. Mulley4, 5, 15, Gordon K. Smyth6, David A. Power3, 8, Paul Saftig16 and Melanie Bahlo6
1 Department of Medicine, Austin Health and Northern Health, Heidelberg, Victoria 3081, Australia
2 Epilepsy Research Centre, The University of Melbourne, West Heidelberg, Victoria 3081, Australia
3 Departments of Neurology, Nephrology and Anatomical Pathology, Austin Health, Heidelberg, Victoria 3081, Australia
4 Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia
5 School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia 5081, Australia
6 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
7 Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3052, Australia
8 Burnett Institute at Austin, Austin Health, Heidelberg, Victoria 3081, Australia
9 Anatomisches Institut, Universität Kiel, D-24098 Kiel, Germany
10 Zentrum Biochemie und Molekulare Zellbiologie, Abt. Biochemie II, Universität Göttingen, 37073 Göttingen, Germany
11 Menzies Research Institute, University of Tasmania 7000, Australia
12 Department of Anatomical Pathology, Alfred Hospital, Prahran, Victoria 3181, Australia
13 Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital McGill University, Montreal H3A 2B4, Canada
14 Laboratory of Biological Psychology, University of Leuven, B-3000 Leuven, Belgium
15 School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5081, Australia
16 Department of Biochemistry, Universität Kiel, D-24098 Kiel, Germany
Corresponding authorAbstract
Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain. Here, we employed a novel combination of molecular strategies to find the responsible gene and show its effects in an animal model. Utilizing only three unrelated affected individuals and their relatives, we used homozygosity mapping with single-nucleotide polymorphism chips to localize AMRF. We then used microarray-expression analysis to prioritize candidates prior to sequencing. The disorder was mapped to 4q13-21, and microarray-expression analysis identified SCARB2/Limp2, which encodes a lysosomal-membrane protein, as the likely candidate. Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes. This study highlights that recessive genes can be identified with a very small number of subjects. The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF. The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies.
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