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A variant in the HS1-BP3 gene is associated with familial essential tremor

From the Center for Human Genetics and Child Neurology (Dr. Higgins, R.Q. Lombardi, J. Pucilowska, and J.P. Rooney), Mid-Hudson Family Health Institute, New Paltz, NY, Parkinson’s Disease Center and Movement Disorders Clinic (Dr. Jankovic), Department of Neurology, Baylor College of Medicine, Houston, TX, and Department of Neurology (Dr. Tan), Parkinson’s Disease and Movement Disorders Program, Singapore General Hospital, Singapore.

Address correspondence and reprint requests to Dr. J.J. Higgins, Center for Human Genetics and Child Neurology, Mid-Hudson Family Health Institute, 279 Main St., Suite 203A, New Paltz, NY 12561; e-mail: jhiggins{at}fpinstitute.org

Background: Genetic linkage studies have identified two susceptibility loci for essential tremor (ET) on chromosomes 3q13 (ETM1) and 2p24.1 (ETM2). Linkage disequilibrium studies in separate population samples from the United States and Singapore suggest an association between ET and loci at ETM2.

Methods: Fine mapping studies were conducted on multiplex and singleton US families linked to ETM2 using newly detected loci within the candidate interval to establish the minimal critical region (MCR) harboring an ET gene. The genes and transcripts within this interval were systematically analyzed by single-strand conformational polymorphism analysis and DNA sequencing.

Results: A 464-kb region between loci D2S2150 and etm1231 was defined as the MCR. The coding regions and flanking intronic splice sites of two genes and seven transcripts in this interval were evaluated for mutations. A missense mutation (828CG) in the transcript FLJ14249 (HS1-BP3) was identified in one US family. This mutation was found in another apparently unrelated US family with ET and was absent in 150 control samples (300 chromosomes). The 828CG mutation causes a substitution of a glycine for an alanine residue in the HS1-BP3 protein. The HS1-BP3 protein binds to proteins that are highly expressed in motor neurons and Purkinje cells and regulate the Ca²⁺/calmodulin-dependent protein kinase activation of tyrosine and tryptophan hydroxylase.

Conclusions: A rare variant in the HS1-BP3 gene that is associated with essential tremor (ET) in two families is reported. This finding will facilitate research on the functional role of this gene and related genes in the pathogenesis of ET.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the February 8 issue to find the title link for this article.

Supported by grant no. R01 NS39353 from NIH (J.J.H.).

This manuscript’s contents are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

Received October 26, 2004. Accepted in final form December 3, 2004.

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