Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A.

@article{Kara2017SevereND,
  title={Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A.},
  author={B{\"u}lent Kara and Çiğdem K{\"o}roğlu and Karita Peltonen and Ruchama Chaya Steinberg and H{\"u}lya Maraş Genç and Maarit H{\"o}ltt{\"a}-Vuori and Ayşe G{\"u}ven and Kristiina Kanerva and Tuğba Kotil and Seyhun Solakoğlu and You Zhou and Vesa M. Olkkonen and Elina Ikonen and Marikki Laiho and Aslıhan Tolun},
  journal={European journal of human genetics : EJHG},
  year={2017},
  volume={25 3},
  pages={
          315-323
        }
}
In two brothers born to consanguineous parents, we identified an unusual neurological disease that manifested with ataxia, psychomotor retardation, cerebellar and cerebral atrophy, and leukodystrophy. Via linkage analysis and exome sequencing, we identified homozygous c.2801C>T (p.(Ser934Leu)) in POLR1A (encoding RPA194, largest subunit of RNA polymerase I) and c.511C>T (p.(Arg171Trp)) in OSBPL11 (encoding oxysterol-binding protein-like protein 11). Although in silico analysis, histopathologic… 
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References

SHOWING 1-10 OF 34 REFERENCES
Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III
TLDR
This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukODYstrophy.
[Niemann-Pick disease type C].
TLDR
Niemann-Pick disease type C is an autosomal recessive neurovisceral lipid storage disorder, but the basic defect has not yet been clarified, and many therapies, i.e. dimethyl sulfoxide, low-cholesterol diet and transplantations, have been challenged but improvement of neurological symptoms have not been reported.
MutationTaster2: mutation prediction for the deep-sequencing age
TLDR
This method takes advantage of the high hybridization efficiency of FISH and the fact that base-pair resolution is usually not needed to uniquely identify a transcript, and will enable the transcriptome to be directly imaged at single-cell resolution in complex samples such as brain tissue.
Cellular pathology of Niemann-Pick type C disease.
Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome
TLDR
These findings identify two additional genes involved in TCS, confirm the genetic heterogeneity of TCS and support the hypothesis that TCS is a ribosomopathy.
A method and server for predicting damaging missense mutations
TLDR
A new method and the corresponding software tool, PolyPhen-2, which is different from the early tool polyPhen1 in the set of predictive features, alignment pipeline, and the method of classification is presented and performance, as presented by its receiver operating characteristic curves, was consistently superior.
...
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