The focus of research in the Raskind laboratory is to identify and study genes responsible for neurobehavioral disorders. We investigate a variety of Mendelian neurogenetic disorders, including spastic paraplegia, movement disorders, neuropathies and ataxias, in a large family set collected over more than 3 decades. We use multiple gene localization techniques combined with exome sequencing and bioinformatics to identify candidate genes responsible for the disease. Supportive evidence for the pathogenicity of the gene is sought through cosegregation studies in the relevant families and screening the gene in other subjects who may have the same disorder. We perform many types of functional studies in cell lines and model organisms to investigate the effect of the mutation on gene function and to delineate steps in the pathogenesis of the disease. We previously discovered that spinocerebellar ataxia type 14 is caused by mutations in protein kinase C gamma and are now studying pathologic differences related to different mutations in mouse models of SCA14 that we generated. More recent gene discoveries include ADCY5 for a heterogeneous movement disorder, ATP6AP2 for a parkinsonian disorder, and SAMD9L for a combined ataxia/bone marrow failure syndrome.
In addition to Mendelian disorders, we study the genetics of dyslexia and familial Alzheimer’s disease. We are using a combination of linkage analysis and genomic sequencing to identify genes that contribute to the risk to develop these common and heterogeneous disorders.
Chen D-H, Brkanac Z, Verlinde CLMJ, Tan X-J, Bylenok L, Nochlin D, Matsushita M, Lipe H, Wolff J, Fernandez M, Cimino PJ, Bird TD, Raskind WH: Missense mutations in the regulatory domain of PKCg: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet 72:839-849, 2003. PMC1180348
Brkanac Z, Spencer D, Shendure J, Robertson PD, Matsushita M, Vu T, Bird TD, Olson MV, Raskind WH: IFRD1 is a candidate gene for SMNA on chromosome 7q22-q23. Am J Hum Genet 84(5):692-697, 2009. PMID: 19409521; PMC2680994
Chen Y-Z, Matsushita MM, Robertson P, Rieder M, Girirajan S, Antonacci F, Lipe H, Eichler EE, Nickerson DA, Bird TD, Raskind WH: Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylate cyclase 5. Arch Neurol 69:630-635, 2012. PMID: 22782511; PMC3508680
Korvatska O, Strand NS, Berndt JD, Strovas T, Chen DH, Leverenz JB, Kiianitsa K, Mata IF, Karakoc E, Greenup JL, Bonkowski E, Chuang J, Moon RT, Eichler EE, Nickerson DA, Zabetian CP, Kraemer BC, Bird TD, Raskind WH. Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS). Hum Molec Genet 2013 Aug 15;22(16):3259-68. PMC3723311.
Chen D-H, Méneret A, Friedman JR, Korvatska O, Gad A, Bonkowski ES, Stessman HA, Doummar D, Mignot C, Anheim M, Bernes S, Davis MY, Damon-Perrière N, Degos B, Grabli D, Gras D, Hisama FM, Mackenzie KM, Swanson PD, Tranchant C, Vidailhet, M, Winesett S, Trouillard O, Amendola LM, Dorschner MO, Weiss M, Eichler EE, Torkamani A, Roze E, Bird TD, Raskind WH. ADCY5-related dyskinesia: broader spectrum and genotype/phenotype correlations. Neurology 85(23):2026-35, 2015. PMID:26537056; PMC4676753.
Chen DH, Below JE, Shimamura A, Matsushita M, Keel SB, Wolff J, Sul Y, Bonkowsjk E, Castella M, Taniguchi T, Nickerson D, Papayannopoulou T, Bird TD, Raskind WH. Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am J Hum Genet 98:1146-1158, 2016. PMC4908176.
Raskind WH, Igo RP, Jr, Chapman NH, Berninger VW, Thomson JB, Matsushita M, Brkanac Z , Holzman T, Brown M, Wijsman EM: A genome scan in multigenerational families with dyslexia: Identification of a novel locus on chromosome 2q that contributes to phonological decoding efficiency. Molec Psychiatry 10:699-711, 2005. PMID: 15753956
Rubenstein K, Rothstein JH, Matsushita M, Berninger VW, Raskind WH, Wijsman EM: Genome scan for spelling deficits: effect of verbal IQ on models of transmission and loci. Behav Genet 41:31-42, 2011. PMC3030654
Rubenstein K, Raskind WH, Berninger VW, Matsushita MM, Wijsman EM. Genome scan for cognitive trait loci of dyslexia: rapid naming and rapid switching of letters, numbers, and colors. Am J Med Genet B Neuropsychiatr Genet 165:345-356, 2014. PMC4053475.