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Query: UMLS:C0013421 (
dystonia
)
8,418
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Hereditary sensory and autonomic neuropathy type VI (HSAN-VI) is a recessive human disease that arises from mutations in the
dystonin
gene (DST; also known as Bullous pemphigoid antigen 1 gene). A milder form of HSAN-VI was recently described, resulting from loss of a single
dystonin
isoform (DST-A2). Similarly, mutations in the mouse
dystonin
gene (Dst) result in severe sensory neuropathy,
dystonia
musculorum (Dstdt). Two Dstdt alleles, Dstdt-Tg4 and Dstdt-27J, differ in the severity of disease. The less severe Dstdt-Tg4 mice have disrupted expression of Dst-A1 and -A2 isoforms, while the more severe Dstdt-27J allele affects Dst-A1, -A2 and -A3 isoforms. As
dystonin
is a cytoskeletal-linker protein, we evaluated microtubule network integrity within sensory neurons from Dstdt-Tg4 and Dstdt-27J mice. There is a significant reduction in tubulin acetylation in Dstdt-27J indicative of microtubule instability and severe microtubule disorganization within sensory axons. However, Dstdt-Tg4 mice have no change in tubulin acetylation, and microtubule organization was only mildly impaired. Thus, microtubule instability is not central to initiation of Dstdt pathogenesis, though it may contribute to disease severity. Maintenance of microtubule stability in Dstdt-Tg4 dorsal root ganglia could be attributed to an upregulation in Dst-A3 expression as a compensation for the absence of Dst-A1 and -A2 in Dstdt-Tg4 sensory neurons. Indeed, knockdown of Dst-A3 in these neurons resulted in a decrease in tubulin acetylation. These findings shed light on the possible compensatory role of
dystonin
isoforms within HSAN-VI, which might explain the heterogeneity in symptoms within the reported forms of the disease.
...
PMID:Dystonin-A3 upregulation is responsible for maintenance of tubulin acetylation in a less severe dystonia musculorum mouse model for hereditary sensory and autonomic neuropathy type VI. 2998 4
Hereditary sensory and autonomic neuropathy (HSAN-VI) is a recessive genetic disorder that arises because of mutations in the human
dystonin
gene (
DST
, previously known as
bullous pemphigoid antigen 1
). Although initial characterization of HSAN-VI reported it as a sensory neuropathy that was lethal in infancy, we now know of a number of heterozygous mutations in
DST
that result in milder forms of the disease. Akin to what we observe in the mouse model
dystonia
musculorum
(
Dst
dt
), we believe that the heterogeneity of HSAN-VI can be attributed to a number of
dystonin
isoforms that the mutation affects. Lack of neuronal isoform
dystonin
-a2 is likely the universal determinant of HSAN-VI because all reported human cases are null for this isoform, as are all
Dst
dt
mouse alleles. Compensatory mechanisms by intact
dystonin
-a isoforms also likely play a role in regulating disease severity, although we have yet to determine what specific effect
dystonin
-a1 and
dystonin
-a3 have on the pathogenesis of HSAN-VI.
...
PMID:HSAN-VI: A spectrum disorder based on dystonin isoform expression. 3204 17
Loss-of-function mutations in
dystonin
(
DST
) can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently,
DST
-related diseases were recognized to be more complex than previously thought because a patient exhibited both neurological and skin manifestations, whereas others display only one or the other. A single
DST
locus produces at least three major
DST
isoforms:
DST-a
(neuronal isoform),
DST-b
(muscular isoform) and
DST-e
(epithelial isoform).
Dystonia
musculorum
(
dt
) mice, which have mutations in
Dst
, were originally identified as spontaneous mutants displaying neurological phenotypes. To reveal the mechanisms underlying the phenotypic heterogeneity of
DST
-related diseases, we investigated two mutant strains with different mutations: a spontaneous
Dst
mutant (
Dst
dt-23Rbrc
mice) and a gene-trap mutant (
Dst
Gt
mice). The
Dst
dt-23Rbrc
allele possesses a nonsense mutation in an exon shared by all
Dst
isoforms. The
Dst
Gt
allele is predicted to inactivate
Dst-a
and
Dst-b
isoforms but not
Dst-e
There was a decrease in the levels of
Dst-a
mRNA in the neural tissue of both
Dst
dt-23Rbrc
and
Dst
Gt
homozygotes. Loss of sensory and autonomic nerve ends in the skin was observed in both
Dst
dt-23Rbrc
and
Dst
Gt
mice at postnatal stages. In contrast,
Dst-e
mRNA expression was reduced in the skin of
Dst
dt-23Rbrc
mice but not in
Dst
Gt
mice. Expression levels of Dst proteins in neural and cutaneous tissues correlated with
Dst
mRNAs. Because
Dst-e
encodes a structural protein in hemidesmosomes (HDs), we performed transmission electron microscopy. Lack of inner plaques and loss of keratin filament invasions underneath the HDs were observed in the basal keratinocytes of
Dst
dt-23Rbrc
mice but not in those of
Dst
Gt
mice; thus, the distinct phenotype of the skin of
Dst
dt-23Rbrc
mice could be because of failure of Dst-e expression. These results indicate that distinct mutations within the
Dst
locus can cause different loss-of-function patterns among
Dst
isoforms, which accounts for the heterogeneous neural and skin phenotypes in
dt
mice and
DST
-related diseases.
...
PMID:Diverse dystonin gene mutations cause distinct patterns of
Dst
isoform deficiency and phenotypic heterogeneity in
Dystonia musculorum
mice. 3248 19
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