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Huntingtin gene CAG repeat size affects autism risk: Family‐based and case–control association study
Ignazio Stefano Piras Chiara Picinelli Raffaele Iennaco Marco Baccarin Paola Castronovo Pasquale Tomaiuolo Francesca Cucinotta Arianna Ricciardello Laura Turriziani Lorenzo Nanetti Caterina Mariotti Cinzia Gellera Carla Lintas Roberto Sacco Chiara Zuccato Elena Cattaneo Antonio M. Persico 《American journal of medical genetics. Part B, Neuropsychiatric genetics》2020,183(6):341-351
The Huntingtin (HTT) gene contains a CAG repeat in exon 1, whose expansion beyond 39 repeats consistently leads to Huntington's disease (HD), whereas normal‐to‐intermediate alleles seemingly modulate brain structure, function and behavior. The role of the CAG repeat in Autism Spectrum Disorder (ASD) was investigated applying both family‐based and case–control association designs, with the SCA3 repeat as a negative control. Significant overtransmission of “long” CAG alleles (≥17 repeats) to autistic children and of “short” alleles (≤16 repeats) to their unaffected siblings (all p < 10?5) was observed in 612 ASD families (548 simplex and 64 multiplex). Surprisingly, both 193 population controls and 1,188 neurological non‐HD controls have significantly lower frequencies of “short” CAG alleles compared to 185 unaffected siblings and higher rates of “long” alleles compared to 548 ASD patients from the same families (p < .05–.001). The SCA3 CAG repeat displays no association. “Short” HTT alleles seemingly exert a protective effect from clinically overt autism in families carrying a genetic predisposition for ASD, while “long” alleles may enhance autism risk. Differential penetrance of autism‐inducing genetic/epigenetic variants may imply atypical developmental trajectories linked to HTT functions, including excitation/inhibition imbalance, cortical neurogenesis and apoptosis, neuronal migration, synapse formation, connectivity and homeostasis. 相似文献
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Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability 总被引:1,自引:15,他引:1
La Spada AR; Peterson KR; Meadows SA; McClain ME; Jeng G; Chmelar RS; Haugen HA; Chen K; Singer MJ; Moore D; Trask BJ; Fischbeck KH; Clegg CH; McKnight GS 《Human molecular genetics》1998,7(6):959-967
X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG
repeat expansion in the first exon of the androgen receptor (AR) gene.
Disease-associated alleles (37-66 CAGs) change in length when transmitted
from parents to offspring, with a significantly greater tendency to shift
size when inherited paternally. As transgenic mice carrying human AR cDNAs
with 45 and 66 CAG repeats do not display repeat instability, we attempted
to model trinucleotide repeat instability by generating transgenic mice
with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions
in their genomic context. Studies of independent lines of AR YAC transgenic
mice with CAG 45 alleles reveal intergenerational instability at an overall
rate of approximately 10%. We also find that the 45 CAG repeat tracts are
significantly more unstable with maternal transmission and as the
transmitting mother ages. Of all the CAG/CTG repeat transgenic mice
produced to date the AR YAC CAG 45 mice are unstable with the smallest
trinucleotide repeat mutations, suggesting that the length threshold for
repeat instability in the mouse may be lowered by including the appropriate
flanking human DNA sequences. By sequence-tagged site content analysis and
long range mapping we determined that one unstable transgenic line has
integrated an approximately 70 kb segment of the AR locus due to
fragmentation of the AR YAC. Identification of the cis - acting elements
that permit CAG tract instability and the trans -acting factors that
modulate repeat instability in the AR YAC CAG 45 mice may provide insights
into the molecular basis of trinucleotide repeat instability in humans.
相似文献
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Wild type huntingtin reduces the cellular toxicity of mutant huntingtin in mammalian cell models of Huntington's disease 总被引:5,自引:0,他引:5
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L. Ho R. Brown M. Maxwell A. Wyttenbach D. Rubinsztein 《Journal of medical genetics》2001,38(7):450-452
OBJECTIVES—Recent data suggest that wild type huntingtin can protect against apoptosis in the testis of mice expressing full length huntingtin transgenes with expanded CAG repeats. It is not clear if this protective effect was confined to particular cell types, or if wild type huntingtin exerted its protective effect in this model by simply reducing the formation of toxic proteolytic fragments from mutant huntingtin.
METHODS—We cotransfected neuronal (SK-N-SH, human neuroblastoma) and non-neuronal (COS-7, monkey kidney) cell lines with HD exon 1 (containing either 21 or 72 CAG repeats) construct DNA and either full length wild type huntingtin or pFLAG (control vector).
RESULTS—Full length wild type huntingtin significantly reduced cell death resulting from the mutant HD exon 1 fragments containing 72 CAG repeats in both cell lines. Wild type huntingtin did not significantly modulate cell death caused by transfection of HD exon 1 fragments containing 21 CAG repeats in either cell line.
CONCLUSIONS—Our results suggest that wild type huntingtin can significantly reduce the cellular toxicity of mutant HD exon 1 fragments in both neuronal and non-neuronal cell lines. This suggests that wild type huntingtin can be protective in different cell types and that it can act against the toxicity caused by a mutant huntingtin fragment as well as against a full length transgene.
Keywords: Huntington's disease; huntingtin; apoptosis 相似文献
METHODS—We cotransfected neuronal (SK-N-SH, human neuroblastoma) and non-neuronal (COS-7, monkey kidney) cell lines with HD exon 1 (containing either 21 or 72 CAG repeats) construct DNA and either full length wild type huntingtin or pFLAG (control vector).
RESULTS—Full length wild type huntingtin significantly reduced cell death resulting from the mutant HD exon 1 fragments containing 72 CAG repeats in both cell lines. Wild type huntingtin did not significantly modulate cell death caused by transfection of HD exon 1 fragments containing 21 CAG repeats in either cell line.
CONCLUSIONS—Our results suggest that wild type huntingtin can significantly reduce the cellular toxicity of mutant HD exon 1 fragments in both neuronal and non-neuronal cell lines. This suggests that wild type huntingtin can be protective in different cell types and that it can act against the toxicity caused by a mutant huntingtin fragment as well as against a full length transgene.
Keywords: Huntington's disease; huntingtin; apoptosis 相似文献
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Human huntingtin derived from YAC transgenes compensates for loss of murine huntingtin by rescue of the embryonic lethal phenotype 总被引:4,自引:4,他引:4
Hodgson JG; Smith DJ; McCutcheon K; Koide HB; Nishiyama K; Dinulos MB; Stevens ME; Bissada N; Nasir J; Kanazawa I; Disteche CM; Rubin EM; Hayden MR 《Human molecular genetics》1996,5(12):1875-1885
Huntington disease (HD) is caused by expansion of a CAG trinucleotide
repeat in exon 1 of a novel gene. The HD protein (huntingtin) plays a
critical role in early embryonic development since homozygous targeted
disruption of the murine HD gene results in embryonic lethality by day 7.5.
To rescue this phenotype by transgene based huntingtin expression it is
therefore essential to express the protein early enough in development in
the appropriate cells. Since YAC based transgenes are known to be regulated
in an appropriate temporal and tissue-specific manner, we sought to rescue
the embryonic lethality by breeding YAC transgenic mice expressing human
huntingtin with mice heterozygous for the targeted disruption. We generated
viable offspring homozygous for the disrupted murine HD gene but expressing
human huntingtin derived from the YAC. This result clearly shows that YAC
transgene based expression of huntingtin occurs prior to 7.5 days
gestation. Additionally, we show that human huntingtin expression in YAC
transgenic mice follows an identical tissue distribution and subcellular
localisation pattern as that of the murine endogenous protein and that
expression levels of 2-3 times endogenous can be achieved. This shows that
human huntingtin under the influence of its native promoter, despite
differences to the murine protein, is functional in a murine background and
can compensate for loss of the murine protein. These results show that YAC
transgenic approaches are a particularly promising route to producing an
animal model for disorders associated with CAG expansion.
相似文献
9.
Gender is known to influence the transmission of trinucleotide repeats in human disease. However, the molecular basis for the parent-of-origin effect associated with trinucleotide repeat expansion is not known. We have followed, during transmission, the fate of the CAG trinucleotide repeat in a transgene containing the exon 1 portion of the human Huntington's disease (HD) gene. Similar to humans, the mouse transmits expansions predominantly through the male germ line. Surprisingly, we find that the CAG repeat size of the mutant human HD gene is different in male and female progeny from identical fathers. Males predominantly expand the repeat whereas females predominantly contract the repeat. In contrast to the classic definition of imprinting, CAG expansion is influenced by the gender of the embryo. Our results raise the possibility that there are X- or Y-encoded factors that influence repair or replication of DNA in the embryo. Gender dependence in the embryo may explain why expansion in HD from premutation to disease primarily occurs through the paternal line. 相似文献
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Cheryl L. Wellington Ryan R. Brinkman John R. O'Kusky Michael R. Hayden 《Brain pathology (Zurich, Switzerland)》1997,7(3):979-1002
Huntington's Disease (HD) is caused by expansion of a CAG trinucleotide beyond 35 repeats within the coding region of a novel gene. Recently, new insights into the relationship between CAG expansion in the HD gene and pathological mechanisms have emerged. Survival analysis of a large cohort of affected and at-risk individuals with CAG sizes between 39 and 50 repeats have yielded probability curves of developing HD symptoms and dying of HD by a certain age. Animals transgenic for the first exon of huntingtin with large CAG repeats lengths have been reported to have a complex neurological phenotype that bears interesting similarities and differences to HD. The repertoire of huntingtin-inter-acting proteins continues to expand with the identification of HIP1, a protein whose yeast homologues have known functions in regulating events associated with the cytoskeleton. The ability of huntingtin to interact with two of its four known protein partners appears to be influenced by CAG length. Caspase 3 (apopain), a key cysteine protease known to play a seminal role in neural apoptosis, has also been demonstrated to specifically cleave huntingtin in a CAG length-dependent manner. Many of these features are combined in a model suggesting mechanisms by whi h the pathogenesis of HD may be initiated. The development of appropriate in vitro and animal models for HD will allow the validity of these models to be tested. 相似文献
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Intraneuronal protein aggregates of the mutated huntingtin in Huntington's disease (HD) brains suggest an overload and/or dysfunction of the ubiquitin-proteasome system (UPS). There is a general inhibition of the UPS in many brain regions (cerebellum, cortex, substantia nigra and caudate-putamen) and skin fibroblasts from HD patients. In the current experiment, the widely used mutant huntingtin-exon 1 CAG repeat HD transgenic mice model (R6/2) (with 144 CAG repeat and exon 1) during late-stage pathology, had increases in proteasome activity in the striatum. However, this discrepancy with HD patient tissue was not apparent in the mutant CAG repeat huntingtin full-length HD (YAC72) transgenic mouse model during post-symptomatic and late-stage pathology, which then also showed UPS inhibition similar to HD patients' brains. In both types of HD model mice, we determined biochemical changes, including expression of brain-derived neurotrophic factor (BDNF) and mitochondrial complex II/III (MCII/III) activities related to HD pathology. We found increases of both BDNF expression, and MCII/III activities in YAC72 transgenic mice, and no change of BDNF expression in R6/2 mice. Our data show that extreme CAG repeat lengths in R6/2 mice is paradoxically associated with increased proteasome activity, probably as a cellular compensatory biochemical change in response to the underlying mutation. Changes in HD patients for UPS function, BDNF expression and MCII/III activity are only partially modeled in R6/2 and YAC72 mice, with the latter at 16 months of age being most congruent with the human disease. 相似文献
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Gillian P. Bates Laura Mangiarini Stephen W. Davies 《Brain pathology (Zurich, Switzerland)》1998,8(4):699-714
An increasing number of neurodegenerative diseases, including Huntington's disease (HD), have been found to be caused by a CAG/polyglutamine expansion. We have generated a mouse model of HD by the introduction of exon 1 of the human HD gene carrying highly expanded CAG repeats into the mouse germ line. These mice develop a progressive neurological phenotype. Neuronal intranuclear inclusions (NII) that are immunoreactive for huntingtin and ubiquitin have been found in the brains of symptomatic mice. In vitro analysis indicates that the inclusions are formed through self aggregation via the polyglutamine repeat into amyloid-like fibrils composed of a cross β-sheet structure that has been termed a polar zipper. Analysis of patient material and other transgenic lines has now shown NII to be a common feature of all of these diseases. In the transgenic models, inclusions are present prior to the onset of symptoms suggesting a causal relationship. In contrast, neurodegeneration occurs after the onset of the phenotype indicating that the symptoms are caused by a neuronal dysfunction rather than a primary cell death. 相似文献
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Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. 总被引:10,自引:0,他引:10
Petersen Asa; Larsen Kristin E.; Behr Gerald G.; Romero Norma; Przedborski Serge; Brundin Patrik; Sulzer David 《Human molecular genetics》2001,10(12):1243-1254
Huntington's disease (HD) is caused by an expanded CAG repeat in exon 1 of the gene coding for the huntingtin protein. The cellular pathway by which this mutation induces HD remains unknown, although alterations in protein degradation are involved. To study intrinsic cellular mechanisms linked to the mutation, we examined dissociated postnatally derived cultures of striatal neurons from transgenic mice expressing exon 1 of the human HD gene carrying a CAG repeat expansion. While there was no difference in cell death between wild-type and mutant littermate-derived cultures, the mutant striatal neurons exhibited elevated cell death following a single exposure to a neurotoxic concentration of dopamine. The mutant neurons exposed to dopamine also exhibited lysosome-associated responses including induction of autophagic granules and electron-dense lysosomes. The autophagic/lysosomal compartments co-localized with high levels of oxygen radicals in living neurons, and ubiquitin. The results suggest that the combination of mutant huntingtin and a source of oxyradical stress (provided in this case by dopamine) induces autophagy and may underlie the selective cell death characteristic of HD. 相似文献
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Recent studies have described Huntington's disease (HD) patients with atypical onset of ataxia. Symptoms in these patients can overlap with those of spinocerebellar ataxia (SCA). We retrospectively examined clinical data for 82 HD probands and found 7 had initially been clinically diagnosed as SCA cases. Clinical features in these patients were further investigated and the number of CAG repeats in the huntingtin (HTT) gene was determined by direct sequencing. Genetic screenings for SCAs in the 7 patients were all negative. By contrast, HTT was heterozygous in each patient. The distribution of CAG number in the 7 patients was statistically the same as that in the other 75 patients. Each of 7 HD patients had presented with atypical onset of ataxia. The mean time from onset to HTT genetic testing was 5.6 ± 5.52 years. Three of the patients developed chorea, but the others did not. Our observations confirm the clinical heterogeneity of HD in Han Chinese. Based on these findings, testing for HTT expansions should be considered for clinically diagnosed SCA patients who test negatively in genetic screening of SCA genes. 相似文献
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McManamny P Chy HS Finkelstein DI Craythorn RG Crack PJ Kola I Cheema SS Horne MK Wreford NG O'Bryan MK De Kretser DM Morrison JR 《Human molecular genetics》2002,11(18):2103-2111
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease, caused by the expansion of a trinucleotide repeat (TNR) in exon 1 of the androgen receptor (AR) gene. This disorder is characterized by degeneration of motor and sensory neurons, proximal muscular atrophy, and endocrine abnormalities, such as gynecomastia and reduced fertility. We describe the development of a transgenic model of SBMA expressing a full-length human AR (hAR) cDNA carrying 65 (AR(65)) or 120 CAG repeats (AR(120)), with widespread expression driven by the cytomegalovirus promoter. Mice carrying the AR(120) transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG repeats showed a mild phenotype. Progressive muscle weakness and atrophy was observed in AR(120) mice and was associated with the loss of alpha-motor neurons in the spinal cord. There was no evidence of neurodegeneration in other brain structures. Motor dysfunction was observed in both male and female animals, showing that in SBMA the polyglutamine repeat expansion causes a dominant gain-of-function mutation in the AR. The male mice displayed a progressive reduction in sperm production consistent with testis defects reported in human patients. These mice represent the first model to reproduce the key features of SBMA, making them a useful resource for characterizing disease progression, and for testing therapeutic strategies for both polyglutamine and motor neuron diseases. 相似文献
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Olivier Simard Marie‐Chantal Grégoire Mélina Arguin Marc‐André Brazeau Frédéric Leduc Isabelle Marois Martin V. Richter Guylain Boissonneault 《Human mutation》2014,35(11):1280-1284
Transient DNA breaks and evidence of DNA damage response have recently been reported during the chromatin remodeling process in haploid spermatids, creating a potential window of enhanced genetic instability. We used flow cytometry to achieve separation of differentiating spermatids into four highly purified populations using transgenic mice harboring 160 CAG repeats within exon 1 of the human Huntington disease gene (HTT). Trinucleotic repeat expansion was found to occur immediately following the chromatin remodeling steps, confirming the genetic instability of the process and pointing to the origin of paternal anticipation observed in some trinucleotidic repeats diseases. 相似文献
19.
Using a modified Repeat Expansion Detection (RED) assay, that was optimized
for individual oligonucleotides, unrelated individuals were systematically
screened for maximal repeat sizes of each of the ten possible trinucleotide
repeats. Cloned trinucleotide repeats were generated and used as standards
for the detectability of single copy trinucleotide repeat fragments. When
the size distributions of trinucleotide repeats were compared to previously
reported data, significant differences were found for the CTT repeat, which
corresponds to the expanded GAA repeat in Friedreich ataxia, as well as for
ATT, CCT and GTT repeats. Since 30-35% of normal individuals have CTG/CAG
trinucleotide repeat sizes of 180 bp or more, we investigated the question
whether small-scale CTG/CAG repeat expansions are detectable on a
population basis by using the RED technique. We blindly screened 20 HD
probands with CAG expansions of the HD gene, ranging in size between 120
and 174 bp, and found that a shift to larger CAG size ranges is clearly
detectable when comparing the distribution of maximal repeat sizes in the
disease group to a control group. Our study, therefore, demonstrates that
the application of the RED assay to a population of probands and a
population of controls allows the detection of small-scale CTG/CAG repeat
expansions in the size range of the expanded HD gene and present in a
single allele. We also provide standards and control data for the detection
of other trinucleotide repeat expansions.
相似文献
20.
Sato T; Oyake M; Nakamura K; Nakao K; Fukusima Y; Onodera O; Igarashi S; Takano H; Kikugawa K; Ishida Y; Shimohata T; Koide R; Ikeuchi T; Tanaka H; Futamura N; Matsumura R; Takayanagi T; Tanaka F; Sobue G; Komure O; Takahashi M; Sano A; Ichikawa Y; Goto J; Kanazawa I 《Human molecular genetics》1999,8(1):99-106
Dentatorubral-pallidoluysian atrophy (DRPLA) is one among an increasing
number of hereditary neurodegenerative diseases determined as being caused
by unstable expansion of CAG repeats coding for polyglutamine stretches. To
investigate the molecular mechanisms underlying CAG repeat instability, we
established three transgenic lines each harboring a single copy of a
full-length human mutant DRPLA gene carrying a CAG repeat expansion. These
transgenic mice exhibited an age- dependent increase (+0.31 per year) in
male transmission and an age- dependent contraction (-1.21 per year) in
female transmission. Similar tendencies in intergenerational instabilities
were also observed in human DRPLA parent-offspring pairs. The
intergenerational instabilities of the CAG repeats may be interpreted as
being derived from the instability occurring during continuous cell
division of spermatogonia in the male, and that occurring during the period
of meiotic arrest in the female. The transgenic mice also exhibited an
age-dependent increase in the degree of somatic mosaicism which occurred in
a cell lineage-dependent manner, with the size range of CAG repeats being
smaller in the cerebellum than in other tissues including the cerebrum,
consistent with observations in autopsied tissues of DRPLA patients. Thus,
the transgenic mice described in this study exhibited age- dependent
intergenerational as well as somatic instabilities of expanded CAG repeats
comparable with those observed in human DRPLA patients, and are therefore
expected to serve as good models for investigating the molecular mechanisms
of instabilities of CAG repeats.
相似文献