ALBERT — All Library Books, journals and Electronic Records Telegrafenberg

Description: Protein aggregate myopathies (PAMs) define muscle disorders characterized by protein accumulation in muscle fibres. We describe a new PAM in a patient with proximal muscle weakness and hypertrophic cardiomyopathy, whose muscle fibres contained inclusions containing myosin and myosin-associated proteins, and aberrant distribution of microtubules. These lesions appear as intact A- and M-bands lacking thin filaments and Z-discs. These features differ from inclusions in myosin storage myopathy (MSM), but are highly similar to those in mice deficient for the muscle-specific RING finger proteins MuRF1 and MuRF3. Sanger sequencing excluded mutations in the MSM-associated gene MYH7 but identified mutations in TRIM63 and TRIM54, encoding MuRF1 and MuRF3, respectively. No mutations in other potentially disease-causing genes were identified by Sanger and whole exome sequencing. Analysis of seven family members revealed that both mutations segregated in the family but only the homozygous TRIM63 null mutation in combination with the heterozygous TRIM54 mutation found in the proband caused the disease phenotype. Both MuRFs are microtubule-associated proteins localizing to sarcomeric M-bands and Z-discs. They are E3 ubiquitin ligases that play a role in degradation of sarcomeric proteins, stabilization of microtubules and myogenesis. Lack of ubiquitin and the 20S proteasome subunit in the inclusions found in the patient suggested impaired turnover of thick filament proteins. Disruption of microtubules in cultured myotubes was rescued by transient expression of wild-type MuRF1. The unique features of this novel myopathy point to defects in homeostasis of A-band proteins in combination with instability of microtubules as cause of the disease.

Print ISSN: 0964-6906

Electronic ISSN: 1460-2083

Topics: Biology , Medicine

Published by Oxford University Press

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

PAPER CURRENT

S·F·X

Fulltext

3

Unknown

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis (2015)

Ramos-Brossier, M., Montani, C., Lebrun, N., Gritti, L., Martin, C., Seminatore-Nole, C., Toussaint, A., Moreno, S., Poirier, K., Dorseuil, O., Chelly, J., Hackett, A., Gecz, J., Bieth, E., Faudet, A., Heron, D., Frank Kooy, R., Loeys, B., Humeau, Y., Sala, C., Billuart, P.

Oxford University Press

In: Human Molecular Genetics

add to mindlist on the mindlist

Details

Publication Date: 2015-01-25

Description: Mutations in interleukin-1 receptor accessory protein like 1 ( IL1RAPL1 ) gene have been associated with non-syndromic intellectual disability (ID) and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTP, regulating the formation and function of excitatory synapses. The aim of this work was to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (ex6) and one point mutation (C31R), identified in patients with ID. Using immunofluorescence and electrophysiological recordings, we examined the effects of IL1RAPL1 mutant over-expression on synapse formation and function in cultured rodent hippocampal neurons. ex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTP that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling because their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTP/IL1RAPL1 interaction in synaptogenesis and as such in ID in the patients.

Print ISSN: 0964-6906

Electronic ISSN: 1460-2083

Topics: Biology , Medicine

Published by Oxford University Press

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

PAPER CURRENT

S·F·X

Fulltext

4

Unknown

TBX1 protein interactions and microRNA-96-5p regulation controls cell proliferation during craniofacial and dental development: implications for 22q11.2 deletion syndrome (2015)

Gao, S., Moreno, M., Eliason, S., Cao, H., Li, X., Yu, W., Bidlack, F. B., Margolis, H. C., Baldini, A., Amendt, B. A.

Oxford University Press

In: Human Molecular Genetics

add to mindlist on the mindlist

Details

Publication Date: 2015-03-20

Description: T-box transcription factor TBX1 is the major candidate gene for 22q11.2 deletion syndrome (22q11.2DS, DiGeorge syndrome/Velo-cardio-facial syndrome), whose phenotypes include craniofacial malformations such as dental defects and cleft palate. In this study, Tbx1 was conditionally deleted or over-expressed in the oral and dental epithelium to establish its role in odontogenesis and craniofacial developmental. Tbx1 lineage tracing experiments demonstrated a specific region of Tbx1-positive cells in the labial cervical loop (LaCL, stem cell niche). We found that Tbx1 conditional knockout ( Tbx1 cKO ) mice featured microdontia, which coincides with decreased stem cell proliferation in the LaCL of Tbx1 cKO mice. In contrast, Tbx1 over-expression increased dental epithelial progenitor cells in the LaCL. Furthermore, microRNA-96 ( miR-96 ) repressed Tbx1 expression and Tbx1 repressed miR-96 expression, suggesting that miR-96 and Tbx1 work in a regulatory loop to maintain the correct levels of Tbx1 . Cleft palate was observed in both conditional knockout and over-expression mice, consistent with the craniofacial/tooth defects associated with TBX1 deletion and the gene duplication that leads to 22q11.2DS. The biochemical analyses of TBX1 human mutations demonstrate functional differences in their transcriptional regulation of miR-96 and co-regulation of PITX2 activity. TBX1 interacts with PITX2 to negatively regulate PITX2 transcriptional activity and the TBX1 N-terminus is required for its repressive activity. Overall, our results indicate that Tbx1 regulates the proliferation of dental progenitor cells and craniofacial development through miR-96-5p and PITX2. Together, these data suggest a new molecular mechanism controlling pathogenesis of dental anomalies in human 22q11.2DS.

Print ISSN: 0964-6906

Electronic ISSN: 1460-2083

Topics: Biology , Medicine

Published by Oxford University Press

Permalink