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Background: Gaps in the knowledge of general practitioners (GPs) in medical genetics prevent the effective utilization of genetic services and increase the risk of liability. Educators recommend that genetics should be integrated into existing teaching programs but the effectiveness of these types of programs is unknown. Aim: The objective of this study was to provide a 2-year educational program for GPs untrained in genetics and to document its impact on genetic knowledge and referrals to a genetic counselor (GC). Methods: Eight genetic lectures series were given at quarterly intervals. Family practice residents received additional training in a genetics clinic, and participated in monthly seminars and bi-annual journal clubs. A pretest–post-test study design (n ¼ 143) was used to evaluate the genetic knowledge of GPs. Post-test scores [mean (%) � SD; 76.1 � 16.8] showed significant improvement compared to pretest scores (61.9 � 19.1). The majority of participants (81%) indicated that the program would have an impact on their clinical practice. The number of referrals to a GC from GPs untrained in genetics did not change over the 2-year period of the program. Conclusion: The results suggest that an integrated educational program in genetics can enhance physicians’ knowledge but may not alter referral patterns to a GC.

Essential tremor (ET) is a movement disorder characterized by a postural or kinetic tremor of the hands, head, or voice. It is typically a familial condition and affects 1% to 4% of the general population. The trait is genetically linked to chromosome 2p in some families. A variant (828CG) in exon 7 of the hematopoietic-specific protein 1 binding protein 3 gene (HS1-BP3) on chromosome 2p recently has been found to segregate with ET in 2 families. To determine the frequency of this variant in a larger series, we studied patients with ET, Parkinson disease (PD), and controls without tremor. Affected singletons representing 73 families from the United States with dominantly inherited ET, 35 individuals with PD, and 304 healthy controls older than age 60 were tested for the 828CG variant in exon 7 of the HS1-BP3 gene by a BseYI restriction enzyme digest of the polymerase chain reaction product. Heterozygous carriers of the mutant allele were identified in 12 individuals with ET (16.4%) and in 1 individual with PD and postural tremor (3%). All of the healthy controls (608 chromosomes) were homozygous for the wild-type allele. The 828CG genetic variant in the HS1-BP3 gene occurs relatively frequently in subjects with ET. The variant may also be found in some individuals with PD and postural tremor. The HS1-BP3 gene plays a putative role in regulating catecholamine and serotonin metabolism, but the functional consequences of the amino acid substitution (A265G) caused by this genetic variant is unknown. © 2005 Movement Disorder Society

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 (828C→G) 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 828C→G 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 Ca 2+ /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.

An ancestral haplotype on chromosome 2p24.1 described in an American sample with familial essential tremor (ET) was analyzed in a different ethnic sample from Singapore. Six polymorphic loci (etm1240, etm1231, etm1234, APOB, etm1241, and etm1242) in a 274-kb interval within an ET gene candidate region (ETM2) were analyzed in Singaporean individuals with a family history of ET (n = 52) and compared to Singaporean controls older than age 65 (n = 49). The allele frequencies were significantly different between cases and controls for the loci etm1234 (p = 0.0001) and APOB (p = 0.0320). An extended haplotype formed by the loci etm1231, etm1234, and APOB occurred with a frequency of 31% in Singaporean cases and in 1.8% of elderly Singaporean controls (p = 0.0005). Haplotype studies in two different population samples suggest that a disease locus for ET lies near or within the 100-kb interval between the loci etm1231 and APOB.

A mild type of autosomal recessive, non-syndromic mental retardation (NSMR) is linked to loci on chromosome 3p. This report delimits the MRT2A minimal critical region to 4.2 Mb between loci D3S3630 and D3S1304. This interval contains nine genes (IL5RA, TRNT1, LRRN1, SETMAR, SUMF1, ITPR1, BHLHB2, EDEM, and MRPS36P1). The results suggest that a mutation does not exist in these genes and that an unknown transcript in the region contributes to the cognitive deficits in NSMR.

The objective of this study was to analyze a sample of unrelated individuals with autosomal dominant essential tremor (ET) for a genetic association with loci in a candidate region (ETM2) on chromosome 2p24.1 that harbors a disease gene for ET. ET is a common movement disorder that is genetically linked to ETM2 in four large families. It is unknown whether this candidate locus is associated with dominantly inherited ET in other individuals. Based on information from previous genetic linkage studies, a linkage disequilibrium study was designed to compare individuals with a family history of ET (n=45) with normal controls (n=70). Three unreported dinucleotide polymorphic loci (etm1240, etm1231, and etm1234) were identified on a physical map of the ETM2 interval in a region of no recombination. The study sample was tested for allele frequency differences by the CLUMP program and haplotypes were analyzed by the FASTEHPLUS program. The allele frequencies were significantly different between ET cases and the control samples for the loci etm1231 (Por =0.0419) and etm1234 (P0.0001). A haplotype formed by the loci etm1231 and etm1234 occurred with a frequency of 29% in cases (n=45) and 9% in a white newborn sample (P0.0001, n=35). The haplotype was not found in normal individuals older than 60 years without tremor (P=0.0063, n=35). This study provides evidence that an ancestral haplotype on chromosome 2p24.1 segregates with the ET disease phenotype in individuals with a family history of the disorder and will facilitate the search for a causative gene.

Essential tremor (ET) is a movement disorder characterized by a postural or kinetic tremor of the hands, head, or voice. It is typically a familial condition and affects 1% to 4% of the general population. The trait is genetically linked to chromosome 2p in some families. A variant (828C--G) in exon 7 of the hematopoietic-specific protein 1 binding protein 3 gene (HS1-BP3) on chromosome 2p recently has been found to segregate with ET in 2 families. To determine the frequency of this variant in a larger series, we studied patients with ET, Parkinson disease (PD), and controls without tremor. Affected singletons representing 73 families from the United States with dominantly inherited ET, 35 individuals with PD, and 304 healthy controls older than age 60 were tested for the 828C--G variant in exon 7 of the HS1-BP3 gene by a BseYI restriction enzyme digest of the polymerase chain reaction product. Heterozygous carriers of the mutant allele were identified in 12 individuals with ET (16.4%) and in 1 individual with PD and postural tremor (3%). All of the healthy controls (608 chromosomes) were homozygous for the wild-type allele. The 828C--G genetic variant in the HS1-BP3 gene occurs relatively frequently in subjects with ET. The variant may also be found in some individuals with PD and postural tremor. The HS1-BP3 gene plays a putative role in regulating catecholamine and serotonin metabolism, but the functional consequences of the amino acid substitution (A265G) caused by this genetic variant is unknown.

Background: Identifying the genetic factors that contribute to memory and learning is limited by the complexity of brain development and the lack of suitable human models for mild disorders of cognition. Methods: Previously, a disease locus was mapped for a mild type of nonsyndromic mental retardation (IQ between 50 and 70) to a 4.2-MB interval on chromosome 3p25-pter in a large kindred. The genes and transcripts within the candidate region were systematically analyzed for mutations by single-strand polymorphism analysis and DNA sequencing. Results: A nonsense mutation causing a premature stop codon in a novel gene ( cereblon ; CRBN ) was identified that encodes for an ATP-dependent Lon protease. The predicted protein sequence is highly conserved across species, and it belongs to a family of proteins that selectively degrade short-lived polypeptides and regulate mitochondrial replication and transcription. One member of the Lon-containing protein family is regionally expressed in the human hippocampus, an important neuroanatomic region that is involved in long-term potentiation and learning. The mutation in the CRBN gene described interrupts an N-myristoylation site and eliminates a casein kinase II phosphorylation site at the C terminus. Conclusions: A gene on chromosome 3p that is associated with mild mental retardation in a large kindred is reported. This finding implicates a role for the ATP-dependent degradation of proteins in memory and learning.

A gene for autosomal dominant familial essential tremor maps to a 9.1 cM interval flanked by loci D2S224 and D2S405 (ETM2) on human chromosome 2p24.3-p24.2. The recombinatorial boundaries of the interval were refined on a radiation hybrid map to a 123 cR minimal critical region (MCR) between D2S224 and D2S2221. High-throughput non-isotopic screening of bacterial artificial chromosomes (BACs) was used to assemble a physical map of the region. A scaffold BAC map of 31 overlapping clones was ordered by their sequence tagged site (STS) content using PCR and Southern blotting. A complementary 3.9 Mb integrated physical map of the human ETM2 region was constructed by identifying GenBank contigs that contained seven BAC DNA sequences and common STSs. Thirty-three transcripts including five known genes (MATN3, LAPTM4A, SDC1, PUM2, and APOB) were identified in the MCR and ordered on an integrated contig by PCR and virtual mapping. This physical map will provide a template for genomic sequencing and the identification of a gene for essential tremor.