title: Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis.
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.
authors.affiliation: Department of Medicine, Austin Health and Northern Health, Heidelberg, Victoria 3081, Australia. s.berkovic@unimelb.edu.au
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.forename: Alicia
authors.initials: A
authors.lastname: Oshlack
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Silver
authors.forename: Marina
authors.initials: M
authors.lastname: Katerelos
authors.forename: Danya F
authors.initials: DF
authors.lastname: Vears
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.forename: Judith
authors.initials: J
authors.lastname: Blanz
authors.forename: Ke Wei
authors.initials: KW
authors.lastname: Zhang
authors.forename: Jim
authors.initials: J
authors.lastname: Stankovich
authors.forename: Renate M
authors.initials: RM
authors.lastname: Kalnins
authors.forename: John P
authors.initials: JP
authors.lastname: Dowling
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.forename: Enrico
authors.initials: E
authors.lastname: Faldini
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Lata
authors.initials: L
authors.lastname: Vadlamudi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Macdonell
authors.forename: Bree L
authors.initials: BL
authors.lastname: Hodgson
authors.forename: Marta A
authors.initials: MA
authors.lastname: Bayly
authors.forename: Judy
authors.initials: J
authors.lastname: Savige
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: David A
authors.initials: DA
authors.lastname: Power
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
mesh_terms: D000818:Animals; D002525:Cerebellar Cortex / Q000473:pathology; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D015870:Gene Expression; D005808:Genes, Recessive; D008040:Genetic Linkage; D005838:Genotype; D005921:Glomerulonephritis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D051116:Receptors, Scavenger / Q000235:genetics*
chemical_list: D051907:Lysosomal Membrane Proteins; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human