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

• Published in: American journal of human genetics Vol. 82; no. 3; pp. 673 - 684
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.03.2008; University of Chicago Press; Cell Press; American Society of Human Genetics
• Subjects: Animals; Biological and medical sciences; Cerebellar Cortex - pathology; Chromosome Mapping; Chromosomes, Human, Pair 4 - genetics; Epilepsy; Fundamental and applied biological sciences. Psychology; Gene Expression; General aspects. Genetic counseling; Genes; Genes, Recessive; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Glomerulonephritis - genetics; Glomerulonephritis - pathology; Humans; Kidney diseases; Lysosomal Membrane Proteins - genetics; Medical genetics; Medical sciences; Mice; Mice, Knockout; Molecular and cellular biology; Mutation; Myoclonic Epilepsies, Progressive - genetics; Myoclonic Epilepsies, Progressive - pathology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Oligonucleotide Array Sequence Analysis; Proteins; Receptors, Scavenger - genetics; Glomerulonephritis; Kidney disease; Human; Glomerulosclerosis; Nervous system diseases; Urinary system disease; Myoclonus; Deficiency; Epilepsy; Involuntary movement; Cerebral disorder; Gene; Central nervous system disease; Genetics; Neurological disorder
• ISSN: 0002-9297; 1537-6605; 1537-6605
• 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.