21 research outputs found
Characterisation of transcriptionally active and inactive chromatin domains in neurons
The tandemly organised ribosomal DNA (rDNA) repeats are transcribed by a
dedicated RNA polymerase in a specialised nuclear compartment, the
nucleolus. There appears to be an intimate link between the maintenance of
nucleolar structure and the presence of heterochromatic chromatin domains.
This is particularly evident in many large neurons, where a single
nucleolus is present, which is separated from the remainder of the nucleus
by a characteristic shell of heterochromatin. Using a combined
fluorescence in situ hybridisation and immunocytochemistry approach, we
have analysed the molecular composition of this highly organised neuronal
chromatin, to investigate its functional significance. We find that
clusters of inactive, methylated rDNA repeats are present inside large
neuronal nucleoli, which are often attached to the shell of
heterochromatic DNA. Surprisingly, the methylated DNA-binding protein
MeCP2, which is abundantly present in the centromeric and perinucleolar
heterochromatin, does not associate significantly with the methylated rDNA
repeats, whereas histone H1 does overlap partially with these clusters.
Histone H1 also defines other, centromere-associated chromatin subdomains,
together with the mammalian Polycomb group factor Eed. These dat
The centromeric/nucleolar chromatin protein ZFP-37 may function to specify neuronal nuclear domains
Murine ZFP-37 is a member of the large family of C2H2 type zinc finger
proteins. It is characterized by a truncated NH2-terminal
Kruppel-associated box and is thought to play a role in transcriptional
regulation. During development Zfp-37 mRNA is most abundant in the
developing central nervous system, and in the adult mouse expression is
restricted largely to testis and brain. Here we show that at the protein
level ZFP-37 is detected readily in neurons of the adult central nervous
system but hardly in testis. In brain ZFP-37 is associated with nucleoli
and appears to contact heterochromatin. Mouse and human ZFP-37 have a
basic histone H1-like linker domain, located between KRAB and zinc finger
regions, which binds double-stranded DNA. Thus we suggest that ZFP-37 is a
structural protein of the neuronal nucleus which plays a role in the
maintenance of specialized chromatin domains
Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation
Objective
To describe the clinical and pathologic features of a novel pedigree with heterozygous STUB1
mutation causing SCA48.
Methods
We report a large pedigree of Dutch decent. Clinical and pathologic data were reviewed, and
genetic analyses (whole-exome sequencing, whole-genome sequencing, and linkage analysis)
were performed on multiple family members.
Results
Patients presented with adult-onset gait disturbance (ataxia or parkinsonism), combined with
prominent cognitive decline and behavioral changes. Whole-exome sequencing identified
a novel heterozygous frameshift variant c.731_732delGC (p.C244Yfs*24) in STUB1 segregating with the disease. This variant was present in a linkage peak on chromosome 16p13.3.
Neuropathologic examination of 3 cases revealed a consistent pattern of ubiquitin/p62-positive
neuronal inclusions in the cerebellum, neocortex, and brainstem. In addition, tau pathology was
present in 1 case.
Conclusions
This study confirms previous findings of heterozygous STUB1 mutations as the cause of SCA48
and highlights its prominent cognitive involvement, besides cerebellar ataxia and movement
disorders as cardinal features. The presence of intranuclear inclusions is a pathologic hallmark
of the disease. Future studies will provide more insight into its pathologic heterogeneity