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Array-Based Gene Discovery with Three Unrelated Subjects Shows SCARB2/LIMP-2 Deficiency Causes Myoclonus Epilepsy and Glomerulosclerosis


Berkovic, SF and Dibbens, LM and Oshlack, A and Silver, JD and Katerelos, M and Vears, DF and Lullmann-Rauch, R and Blanz, J and Zhang, KW and Stankovich, J and Kalnins, RM and Dowling, JP and Andermann, E and Andermann, F and Faldini, E and D'Hooge, R and Vadlamudi, L and Macdonell, RA and Hodgson, BL and Bayly, MA and Savige, J and Mulley, JC and Smyth, GK and Power, DA and Saftig, P and Bahlo, M, Array-Based Gene Discovery with Three Unrelated Subjects Shows SCARB2/LIMP-2 Deficiency Causes Myoclonus Epilepsy and Glomerulosclerosis, American Journal of Human Genetics, 82, (3) pp. 673-684. ISSN 0002-9297 (2008) [Refereed Article]

DOI: doi:10.1016/j.ajhg.2007.12.019


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. © 2008 The American Society of Human Genetics.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Genetics not elsewhere classified
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Stankovich, J (Dr Jim Stankovich)
ID Code:52432
Year Published:2008
Web of Science® Times Cited:165
Deposited By:Menzies Institute for Medical Research
Deposited On:2008-07-10
Last Modified:2009-04-23

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