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

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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 (2008) 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

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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.

Item Type: Article
Journal or Publication Title: American Journal of Human Genetics
Page Range: pp. 673-684
ISSN: 0002-9297
Identification Number - DOI: 10.1016/j.ajhg.2007.12.019
Date Deposited: 14 Jul 2008 22:54
Last Modified: 18 Nov 2014 03:45
URI: http://eprints.utas.edu.au/id/eprint/7043
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