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The datasets analyzed during the current study are available from the corresponding author on reasonable request.

A goljsn cloning approach utilizing genome-wide linkage, homozygozity mapping and whole transcrlpt sequencing was used for genetic characterization. The impact of a calmodulin-binding transcription activator 2, CAMTA2 isoform 2, hypomorphic mutation on mRNA and protein abundance was studied using fluorescent reporter expression cassettes. Linkage analysis and homozygozity mapping localized the disease allele to a 2. Mutation of CAMTA2 resulting in post-transcriptional inhibition of its own gene activity likely underlies a novel syndromic tremulous dystonia.

The online version of this article Currently, classification of dystonia relies upon phenomenology rather than etiology. A natural bifurcation is made based upon whether, with the exception of tremor, it is the sole motor feature isolated dystonia or is accompanied by other movement disorders including myoclonus combined dystonia [ 1 ]. Gkljan advent of next generation sequencing has led to rapid expansion of phenotypic and genotypic subsets of syndromes primarily characterized as giljan or combined dystonias with more than 20 loci DYT1-DYT27; trabscript are redundant identified to date [ 23 ].

DYT4 TUBB4A may present as an autosomal dominant disorder in adolescence or early adulthood with prominent laryngeal dysphonia and craniocervical, segmental, or generalized dystonia [ 1213 ]. A rare recessively inherited generalized isolated dystonia results from mutation of PRKRA DYT16 and is characterized by early onset and frequent association with dystonia-Parkinsonism [ 21415 ].

Goljan Audio Lectures and High Yield Notes

Dystonic movements are also associated with mutations of ADCY5identified as the likely cause of a novel movement disorder, familial dyskinesia with facial myokimia FDFM [ 1718 ].

We previously reported a consanguineous extended family having a novel autosomal recessive syndromic tremulous dystonia with spasticity and white matter disease [ 19 ]. In this study, we further delineate and genetically characterize the syndrome, identifying CAMTA2 as a novel candidate gene for a syndromic tremulous dystonia, and describe its clinical course and prognosis over a long follow-up period.

The families originated from the Eastern part of the Arabian Peninsula.

The detailed clinical description was previously reported [ 19 ]. Speech became dysarthric and tremulous. The volitional movement was exacerbated by posture and action. Initially, gait was not impaired. Intelligence, personality, and memory were not affected apart from paranoia and depression in two individuals. Granscript addition, there was variable focal or segmental dystonia with retrocollis shoulder elevation and hyperextension of the fingers.

Sensory examination was intact and there was no truncal ataxia.

The patients were cognitively intact, they were able to finish college, hold independent jobs, get married, and have children. Trxnscript, organic acid, and lysosomal enzyme studies were normal. Visual and somatosensory evoke potentials showed evidence of prolonged central latencies. Accelerometric goljaan from the outstretched hand showed 4-Hz tremors. MRI of the brain showed similar abnormalities in all.

There was mild symmetrical and confluent white-matter abnormalities sparing the U-fibers and involving the white matter of centrum semiovale, internal capsule, and ventral pons.

These findings are not characteristic in any of the classic leukodystrophies. MR spectroscopy showed no lactate peak or other abnormalities. Patients failed to respond to therapeutic trials of ethanol or toljan. However, some symptomatic benefits were noted with high-dose propranolol, gabapentin, and clonazepam.

Patients exhibited generalized hyperreflexia with an extensor planter response being noted. Identification of a dystonia-associated locus on chromosome Linkage analysis of the nuclear families with three and two affected individuals Fig. Based upon runs of homozygosity shared by all the affected and absent in unaffected transcrlpt Fig.


Whole exome sequencing of individual IV: These were further filtered to exclude all variants present outside our defined ROH chr Within the critical interval chr By only focusing on homozygous changes annotated as non-synonymous, splicing variants, frameshift insertions or deletions, and nonsense variants, we decreased the number of candidate variants to 1.


This homozygous variant was identified in 56 reads, was confirmed by Sanger sequencing Fig. CAMTA2 has many transcript variants only six 1, 2, 3, 4, 7, and 10 of which are protein coding https: The resulting amino terminus amino acid sequences of these transcript variants are aligned and show that the first 12 amino acids of transcript variant 2 are not shared by the other protein coding transcript variants Fig.

Despite the absence of linkage or homozygozity mapping data to suggest involvement of any known dystonia loci, WES of all affected individuals, parents, and unaffected siblings from both nuclear families was undertaken.

More importantly, the mutant variant secondary structure has only two stems and a wider loop as opposed to the three stem-tight loop of the wild type Fig.

We observed significant reduction in protein fluorescence levels; Fig. PCR amplification of each protein coding isoform of CAMTA2 indicated differential expression of isoform 2 which was only detected in the vermis cerebellum, left and right cerebellum, cerebral cortex, olfactory lobe, and cerebellar peduncles. Expression of this variant was not detected in the corpus callosum, hippocampus, occipital, or frontal lobes Fig.

GAPDH expression was used as an internal control for PCR amplification and specificity for each isoform confirmed by Sanger sequencing of amplicons as shown for transcript variant 2 Fig. We have described the clinical and genetic characteristics of a novel autosomal recessive familial tremulous dystonia syndrome, characterized by juvenile onset tremulous dystonia with spasticity and white matter disease.

Phenotypically, the syndrome was heterogeneous within the families studied with all affected individuals displaying variable forms of both focal or segmental dystonia and coarse, asymmetrical, generalized tremor involving the head, neck and extremities [ 19 ]. Isolated dystonia is a classification reserved for exclusive occurrence of dystonia with the exception of tremor, whereas combined dystonia includes additional symptoms such as myoclonus or Parkinsonism by which it is further sub-classified [ 2 ].

Disease in the families we report is best characterized as a novel syndromic tremulous dystonia. The phenotype that combines dystonia, tremor, spasticity, and white matter disease clearly defines a novel clinical syndrome [ 19 ]. The novel nature of this syndrome is highlighted if not confirmed by identification of a previously undescribed single gene disorder segregating in an autosomal recessive manner within the families studied LOD score 4.

Whole exome and Sanger sequencing identified a homoallelic hypomorphic mutation c. CAMTA proteins include multiple functional amino acid domains that are evolutionarily conserved including nuclear localization signals, nuclear export signals, a unique DNA binding domain CG-1, TIG-1 involved in protein dimerization, and ANK ankyrin repeats involved in protein-protein interactions [ 21 — 24 ].

Cardiac hypertrophy as a consequence transcriptional reprogramming of cardiac gene expression by CAMTA2 interaction with class II histone deacetylase has been reported [ 26 ].

It is not surprising that CAMTA2 is strongly expressed in both developing and adult murine retina; however, its function in this context remains unknown. Given the diverse expression and activity of GPCRs, it is reasonable to speculate that regulation of this rranscript of molecule by Tfanscript may modulate cellular growth and franscript as evidenced in cardiac hypertrophy [ 26 ]. The expression pattern and function of each isoform golajn unknown. Our results clearly indicated that the CAMTA2 mutant affected processes downstream of mRNA transcription, most likely translation trasncript protein levels were dramatically reduced while there was no effect on mRNA levels Fig.

As protein expression was severely impacted without any alteration in the coding region i. These activities are lost in transcriot case of the mutant variant. In general, mutations near initiation regions can dramatically affect translation. Context sequence upstream of the initiation codon can modulate the scanning activity of the 40S ribosomal subunit affecting translation; mutations in this region, such as those in the Kozak consensus sequence that direct ribosomes to initiate protein synthesis, negatively affect translation initiation [ 29 ].

Further support for the pathogenicity or association of the CAMTA2 variant with the phenotype described for which we propose the name Bohlega Syndrome in affected members of the family studied comes from the expression pattern of CAMTA2 transcript variant 2 in human brain sub-regions where it is expressed in the vermis cerebellum, left and right cerebellum, cerebral cortex, olfactory lobe, and cerebellar peduncles Fig. Expression of this isoform was not detected in the corpus callosum, hippocampus, and occipital or frontal lobes Fig.


Dystonia and Parkinsonism, including tremor, have largely been attributed to dysfunction of the basal ganglia. Anatomical studies have identified connections from the basal ganglia and cerebellum via the thalamus to the cortex [ 33 ].

Of note, the ability of CAMTA2 knockout mice to mount a hypertrophic response to cardiac stress such as aortic banding is severely compromised [ 27 ].

In the affected individuals from our study, absence transcrilt any clinical cardiac symptoms extends the apparent discordance between the human and mouse phenotypes, albeit the mouse phenotype was induced by severe transxript aortic banding [ 27 ].

However, the mouse ENCODE consortium mapped transcription factor binding and other regulatory domains across the mouse genome and compared them with the human genome.

Goljan pathology audio and notes – Step 1 – USMLE Press

While they identified substantial conservation, they also identified a goljann degree of divergence between mouse and man in transcription and transcription regulation [ 34 ]. Therefore, differences in mouse and human phenotypes associated with transcrlpt such as CAMTA2 involving transcription or transcription regulation should not be unexpected. Our study identifies a novel dystonia locus CAMTA2 that opens a new line of investigation associated with the role of CAMTA2 in the growth, differentiation, survival, and function of cells and their cellular mechanisms within the brain as related to movement disorders.

It also highlights the value of rare inherited disorders in providing insight into more common disease states such as dystonia and tremor. Five patients from a consanguineous extended family two nuclear families Fig. They were diagnosed with familial tremulous dystonia. The other clinical, neurophysiological, and laboratory methodology may be reviewed from the previously published clinical paper [ 19 ].

For linkage analysis, the extended family was broken down to reflect the hranscript consanguineous nuclear families, with both independent LOD scores and a combined total LOD score being calculated, in a single multipoint analysis of both nuclear families. Reads were mapped to UCSC hg19 http: Based upon the consanguineous inbred pedigree and a clear autosomal recessive inheritance pattern in the family studied, the resultant variant caller file vcf was filtered to include only homozygous variants in the critical interval on chromosome identified by linkage and homozygosity mapping, within the pre-determined ROH transcripy by all affected individuals only.

Included variants were further selected based upon pathogenicity predicted by Polyphen2 http: Potential causative variant s were validated by Sanger sequencing and further vetted for familial segregation based upon autosomal recessive inheritance. CAMTA2 transcript variant 2 is a human isoform and aligns with the human reference sequence of this gene. The reverse primer is complementary to a downstream region of the poly A site on the vector.

Briefly, PCR was performed with the following conditions: The PCR products were run on a 1. Cells were transfected with purified reporter constructs. At these conditions, no effect on cell viability was observed. All transfections were performed in several replicates as indicated in the text. Fluorescence were goljsn by the BD imaging pathway and quantified using the Proxcell imaging segmentation and quantification program [ 38 ].

The following primers were used: In all cases, relative quantification of expression was determined using the standard curve method and the values obtained were within both detectable and linear range.

Briefly, PCR mixtures containing 2. Primer information is available on request. Representative bands were sequenced to confirm amplicon specificity. The authors would like to thank the family members for their participation in this study.