Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis

Berkovic, Samuel F., Dibbens, Leanne M., Oshlack, Alicia, Silver, Jeremy D., Katerelos, Marina, Vears, Danya F., Lüllmann-Rauch, Renate, Blanz, Judith, Zhang, Ke Wei, Stankovich, Jim, Kalnins, Renate M., Dowling, John P., Andermann, Eva, Andermann, Frederick, Faldini, Enrico, D'Hooge, Rudi, Vadlamudi, Lata, Macdonell, Richard A., Hodgson, Bree L., Bayly, Marta A., Savige, Judy, Mulley, John C., Smyth, Gordon K., Power, David A., Saftig, Paul and Bahlo, Melanie (2008) Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. The American Journal of Human Genetics, 82 3: 673-684. doi:10.1016/j.ajhg.2007.12.019


Author Berkovic, Samuel F.
Dibbens, Leanne M.
Oshlack, Alicia
Silver, Jeremy D.
Katerelos, Marina
Vears, Danya F.
Lüllmann-Rauch, Renate
Blanz, Judith
Zhang, Ke Wei
Stankovich, Jim
Kalnins, Renate M.
Dowling, John P.
Andermann, Eva
Andermann, Frederick
Faldini, Enrico
D'Hooge, Rudi
Vadlamudi, Lata
Macdonell, Richard A.
Hodgson, Bree L.
Bayly, Marta A.
Savige, Judy
Mulley, John C.
Smyth, Gordon K.
Power, David A.
Saftig, Paul
Bahlo, Melanie
Title Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis
Journal name The American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2008-03-03
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2007.12.019
Volume 82
Issue 3
Start page 673
End page 684
Total pages 12
Place of publication Cambridge, MA, U.S.A.
Publisher Cell Press
Language eng
Subject 0604 Genetics
Formatted abstract
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.
Keyword Action myoclonus-renal failure syndrome
SCARB2/LIMP-2
Myoclonus epilepsy
Glomerulosclerosis
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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Created: Tue, 12 Jan 2010, 14:41:24 EST by Natalie Holt on behalf of Faculty Of Health Sciences