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EXPEDITED ARTICLES: J. J. Higgins, R. Q. Lombardi, J. Pucilowska, J. Jankovic, E. K. Tan, and J. P. Rooney A variant in the HS1-BP3 gene is associated with familial essential tremor Neurology 2005; 64: 417-421 [Abstract] [Full text] [PDF]

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Reply to Shatunov et al

Joseph J. Higgins, MD, Roni Q. Lombardi, Joanna Pucilowska, Eng King Tan   (7 June 2005)

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

Alexey Shatunov, Joseph Jankovic, Rodger Elble, Nyamkhishig Sambuughin, Andrew Singleton, Mark Hallett, and Lev Goldfarb   (7 June 2005)

Reply to Shatunov et al 7 June 2005
Joseph J. Higgins, MD, Mid-Hudson Family Health Institute 279 Main Street, New Paltz, NY, Roni Q. Lombardi, Joanna Pucilowska, Eng King Tan Send Correspondence to journal: Re: Reply to Shatunov et al jhiggins{at}fpinstitute.org Joseph J. Higgins, MD, et al.	Shatunov et al question the association between familial essential tremor (ET) and a variant in the HS1-BP3 gene [1] by citing unpublished data on genetic linkage studies performed on seven families from the United States with the disorder. ET was presumably linked to a locus on chromosome 2p24 locus in one of these families with 14 affected individuals. The authors can not judge whether the phenotype in this family was linked to the same loci on chromosome 2p (ETM2) reported previously by Higgins et al. in families and populations with ET. [2-4] The linkage data and the pedigree structure of the other six unpublished families with some affected individuals with the Ala265Gly variant are not available. The authors encourage Shatunov et al. to publish their family studies because we can not adequately comment on the validity of their conclusions without a critical review of their experimental design and methods. For example, the pedigree structures in the article by Higgins et al. [1] were unusual because both parents in the first generation carried the trait and one parent (individual I-2) was either hemizygous or homozygous for the rare Gly/Gly variant. The possibility of digenic inheritance was suggested since these affected spouses (Figure 1A) transmitted different chromosome 2 loci to their subsequent offspring. Another potential methodological difference was that the control population was carefully chosen by Higgins et al [1]to include only healthy individuals older than age 60 without tremor. The rationale for the selection of this elderly population was based on the zero genetic risk of developing familial essential tremor after the age of 60.5 Comparing the allele frequency differences between these controls and individuals with familial ET should eliminate the chance of including a presymptomatic individual in the control group. This is particularly important since essential tremor is a common trait that may be present in some populations [6] with a similar allele frequency as cited by Shatunov et al. for the Ala265Gly variant. We thank Shatunov et al for their interest in our article and agree that an ET phenotype is in linkage disequilibrium with the Ala265Gly HS1-BP3 variant and is not a causative mutation. However, there is a possibility that ET may involve digenic or polygenic inheritance and include a role for modifier genes. The functional role of the HS1-BP3 gene in regulating catecholamine and serotonin metabolism is admittedly intriguing and needs further study. References 1. Higgins JJ, Lombardi RQ, Pucilowska J, Jankovic J, Tan EK, Rooney JP. A variant in the HS1-BP3 gene is associated with familial essential tremor. Neurology 2005;64:417-421. 2. Higgins JJ, Pho LT, Nee LE. A gene (ETM) for essential tremor maps to chromosome 2p22-p25. Mov Disord 1997;12:859-864. 3. Higgins JJ, Jankovic J, Lombardi RQ, et al. Haplotype analysis of the ETM2 locus in familial essential tremor. Neurogenetics 2003;4:185-189. 4. Higgins JJ, Lombardi RQ, Tan EK, Jankovic J, Pucilowska J, Rooney JP. Haplotype analysis at the ETM2 locus in a Singaporean sample with familial essential tremor. Clin Genet 2004;66:353-357. 5. Bain PG, Findley LJ, Thompson PD, et al. A study of hereditary essential tremor. Brain 1994;117 ( Pt 4):805-824. 6. Benito-Leon J, Bermejo-Pareja F, Morales JM, Vega S, Molina JA. Prevalence of essential tremor in three elderly populations of central Spain. Mov Disord 2003;18:389-394.
A variant in the HS1-BP3 gene is associated with familial essential tremor 7 June 2005
Alexey Shatunov, National Institute of Neurological Disorders and Stroke, NIH 5625 Fishers Lane, Room 4S06, Bethesda, MD 20892-9404, Joseph Jankovic, Rodger Elble, Nyamkhishig Sambuughin, Andrew Singleton, Mark Hallett, and Lev Goldfarb Send Correspondence to journal: Re: A variant in the HS1-BP3 gene is associated with familial essential tremor shatunoa{at}ninds.nih.gov Alexey Shatunov, et al.	Higgins et al [1] reported an association between essential tremor (ET) and a rare Ala265Gly variant of the HS1-BP3 gene located in the 2p24 chromosomal region. We previously performed a genomewide linkage study in seven American families with ET and identified one family having positive linkage to the 2p24 locus. Of 14 affected members of this family, none carried the Ala265Gly variant, as determined by sequencing of the HS1-BP3 coding region. In a second family, in which linkage to 2p24 could not be excluded, the Ala265Gly substitution was detected in 3 of 13 patients. Of 22 tested ET patients from the remaining families, in which there was no linkage to 2p24, two had the Ala265Gly substitution. In each family, there were affected members having additional amino acid altering substitutions in the HS1-BP3 gene, Pro296Leu and Glu297Asp. However, neither the original Ala265Gly nor any of the other polymorphisms nor a haplotype composed of all three polymorphisms segregated with ET in any of these families. Screening of 92 unrelated American control individuals, all adults, by direct sequencing resulted in establishing the following genotype frequencies for the Ala265Gly variant: Ala/Ala - 88%; Ala/Gly - 11%; Gly/Gly - 1%. The results for the Pro296Leu polymorphism: Pro/Pro - 48%; Pro/Leu - 46%; Leu/Leu - 6%; and for Glu297Asp: Glu/Glu - 52%, Glu/Asp - 36%, Asp/Asp - 12%. Since no evidence of co-transmission was observed in the affected families, and considering that the frequency of the Ala265Gly allele in the general population is much higher than initially reported, we were unable to confirm that the identified changes in the HS1-BP3 gene, including Ala265Gly, are associated with ET. It is possible that, in some families, the HS1-BP3 polymorphisms are in linkage disequilibrium with an unknown ET-causative gene. Reference 1. Higgins JJ, Lombardi RQ, Pucilowska J, et al. A variant in the HS1-BP3 gene is associated with familial essential tremor. Neurology 2005; 64:417-421.