14 research outputs found
Proteomic Analysis of Brain and Cerebrospinal Fluid from the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Potential Biomarkers
Clinical trials have
been conducted for the neuronal ceroid lipofuscinoses
(NCLs), a group of neurodegenerative lysosomal diseases that primarily
affect children. Whereas clinical rating systems will evaluate long-term
efficacy, biomarkers to measure short-term response to treatment would
be extremely valuable. To identify candidate biomarkers, we analyzed
autopsy brain and matching CSF samples from controls and three genetically
distinct NCLs due to deficiencies in palmitoyl protein thioesterase
1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease), and CLN3
protein (CLN3 disease). Proteomic and biochemical methods were used
to analyze lysosomal proteins, and, in general, we find that changes
in protein expression compared with control were most similar between
CLN2 disease and CLN3 disease. This is consistent with previous observations
of biochemical similarities between these diseases. We also conducted
unbiased proteomic analyses of CSF and brain using isobaric labeling/quantitative
mass spectrometry. Significant alterations in protein expression were
identified in each NCL, including reduced STXBP1 in CLN1 disease brain.
Given the confounding variable of post-mortem changes, additional
validation is required, but this study provides a useful starting
set of candidate NCL biomarkers for further evaluation
Updated pedigree of the Parry family.
<p>Individuals included in this study are indicated with star symbols on top of individual's number. The proband is marked with an arrow. One of the individuals in generation V was marked V-1A in order to match the individual numbers with the ones in the initially published Parry pedigree, reference 5.</p
Identification of DNA variants in <i>DNAJC5</i> and <i>PRPF6</i>.
<p>a) Schematic of the region on chromosome 20 containing <i>DNAJC5</i> and <i>PRPF6</i> in close proximity. b) Sanger sequence traces of the identified segregating variants in <i>DNAJC5</i> and <i>PRPF6</i>. c) The two very rare changes identified in the Parry family Leu116del (in <i>DNAJC5</i>) and N477S (in <i>PRPF6</i>) were highly conserved in different species. A second change in <i>DNAJC5</i>, Leu115Arg, was also highly conserved.</p
Clinical manifestations in probands from the families or sporadic affected individuals included in the study.
<p>Clinical manifestations in probands from the families or sporadic affected individuals included in the study.</p
Haplotype reconstruction with genetic markers in <i>DNAJC5</i>.
<p>Two informative homozygous discordant genotypes close to the Leu116del change indicate that the Parry family does not share a haplotype with either of the two families reported in Noskova et al supporting a mutational hotspot rather than a founder effect. Grey: Noskova et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029729#pone.0029729-Noskova1" target="_blank">[4]</a> haplotypes; Red: Discordant homozygous genotypes; all markers appear in their genomic order from centromere to telomere.</p
Haplotype reconstruction with genetic markers in <i>DNAJC5</i>.
<p>Three homozygous discordant genotypes close to the Leu115Arg change indicate that family BD319 does not share a haplotype with the three families reported in Noskova et al supporting a mutational hotspot rather than a founder effect. Grey: Noskova et al haplotypes; Red: Discordant homozygous genotypes; all markers appear in their genomic order from centromere to telomere.</p
Laboratory, neuropathology studies and DNAJC5 mutation status of probands from the families included in the study.
<p>*EM = Electron microscopy;</p><p>**GROD = Granular osmophilic deposits.</p
Correction: Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry
<p>Correction: Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry</p
Summary of the 187 patients included in the genetic study.
<p>Summary of the 187 patients included in the genetic study.</p
Ages at unsupported sitting acquisition in each group of patients defined by their genotype.
<p>Cumulative probability of acquiring unsupported sitting by patients presenting the E815K mutation, compared to patientsmutation (3b). Patients with the E815K mutation are likely to gain unsupported sitting at a later age than patients in each of the other groups (respectively P = 0.0002 and P = 0.0020).</p