PMC:3654953 / 22971-27122 JSONTXT

{"project":"AxD_symptoms","denotations":[{"id":"T59","span":{"begin":155,"end":172},"obj":"Phenotype"},{"id":"T60","span":{"begin":174,"end":191},"obj":"Phenotype"},{"id":"T61","span":{"begin":313,"end":325},"obj":"Phenotype"},{"id":"T62","span":{"begin":559,"end":579},"obj":"Phenotype"},{"id":"T63","span":{"begin":589,"end":606},"obj":"Phenotype"},{"id":"T64","span":{"begin":2356,"end":2385},"obj":"Phenotype"},{"id":"T65","span":{"begin":2619,"end":2635},"obj":"Phenotype"},{"id":"T66","span":{"begin":2862,"end":2879},"obj":"Phenotype"},{"id":"T67","span":{"begin":3005,"end":3022},"obj":"Phenotype"},{"id":"T68","span":{"begin":3273,"end":3290},"obj":"Phenotype"},{"id":"T69","span":{"begin":3430,"end":3447},"obj":"Phenotype"}],"attributes":[{"id":"A59","pred":"hp_id","subj":"T59","obj":"http://purl.obolibrary.org/obo/HP_0001251"},{"id":"A61","pred":"hp_id","subj":"T61","obj":"http://purl.obolibrary.org/obo/HP_0012332"},{"id":"A60","pred":"hp_id","subj":"T60","obj":"http://purl.obolibrary.org/obo/HP_0010530"},{"id":"A62","pred":"hp_id","subj":"T62","obj":"http://purl.obolibrary.org/obo/HP_0100543"},{"id":"A66","pred":"hp_id","subj":"T66","obj":"http://purl.obolibrary.org/obo/HP_0002180"},{"id":"A69","pred":"hp_id","subj":"T69","obj":"http://purl.obolibrary.org/obo/HP_0002180"},{"id":"A64","pred":"hp_id","subj":"T64","obj":"http://purl.obolibrary.org/obo/HP_0007354"},{"id":"A67","pred":"hp_id","subj":"T67","obj":"http://purl.obolibrary.org/obo/HP_0002180"},{"id":"A65","pred":"hp_id","subj":"T65","obj":"http://purl.obolibrary.org/obo/HP_0003202"},{"id":"A63","pred":"hp_id","subj":"T63","obj":"http://purl.obolibrary.org/obo/HP_0100022"},{"id":"A68","pred":"hp_id","subj":"T68","obj":"http://purl.obolibrary.org/obo/HP_0002180"}],"text":"Discussion\nA substantial fraction of AOAD patients are sporadic, the most frequent symptoms being related to bulbar dysfunction, pyramidal involvement and cerebellar ataxia. Palatal myoclonus is frequent in, and highly suggestive of, AOAD [4]. Other findings include cognitive deterioration, sleep disorders, and dysautonomia. The course is slowly progressive and fluctuations may occur. Ultimately, the diagnosis is strongly suggested by a typical MRI pattern, and confirmed by GFAP gene analysis. In our family, Pt1 has been suffering of slowly progressive cognitive impairment and mild movement disorder, whereas her younger half-brother (Pt2) has severe MND. In spite of clinical diversity, the cardinal MRI features of AOAD [24] were present in both. The absence of mutation in the GFAP-α encoding gene prompted us to perform exome-NGS and eventually identify a unique mutation in alternative GFAP ex7A, not present in the healthy mother tested DNAs and with a deleterious outcome in a cellular model. These are in fact the first cases associated with a mutation in the GFAP-ϵ variant (GFAP-ϵR430H). Whilst this finding supports the idea that AOAD is almost invariably associated with abnormalities of GFAP, it also expands the spectrum of variants that should be included in the diagnostic screening. Due to the pedigree structure, the mutation has very likely been transmitted by maternal germinal mosaicism, since it was absent in other available family members, including the healthy mother of the two patients.\nThe clinical diversity in our two half-siblings was as remarkable as to suggest that differential segregation of other gene variants could influence phenotypic expression. A prioritized variant found by in-silico data mining was in HDAC6. A hemizygous HDAC6P856S change, found in Pt2, and absent in Pt1, was associated with decreased tubulin-specific deacetylase activity [22]. Through deacetylation of α-tubulin, HSP90, and other substrates, and binding to ubiquitinated proteins that are then transported into, and degraded by, the aggresome, HDAC6 plays a role in a number of important homeostatic and signaling pathways, including axonal transport, redox signaling, misfolded-protein response, and autophagy [25,26]. Interestingly, the RNA-binding modulator factors TDP-43 and FUS/TLS, whose mutations are associated with familial amyotrophic lateral sclerosis (ALS), have HDAC6 mRNA as a specific substrate [27]. A Drosophila model in which TDP-43 is silenced shows decreased HDAC6 expression, [28] and HDAC6 overexpression is able to rescue the phenotype of a Drosophila model of spinobulbar muscular atrophy [6].\nTaken together, these observations indicate HDAC6 as a master regulator of different neuroprotective mechanisms, partly mediated by controlling MTOC biogenesis and function, [23] and predict a role for defective HDAC6 in neurodegeneration, particularly in MND [26]. As for mammalian models, although a first strain of HDAC6 knockout (KO) mice presented no sign of neurodegeneration, [29] altered emotional behaviors suggested a contribution of HDAC6 to maintain proper neuronal activity [30]. Moreover, a second KO HDAC6 strain displayed ubiquitin-positive aggregates and increased apoptosis of brain nerve cells, both hallmarks of neurodegeneration, starting from 6 months of age [31]. These and other results suggest for HDAC6 a complex role in contributing to either neuroprotection or neurodegeneration, depending on the specific pathological condition [7,26,32]. These opposite effects can indeed hamper the development of therapeutic strategies based on HDAC6 modulation [7].\nAlbeit preliminary, our own results support the interesting hypothesis that the HDAC6P856S protein variant may be acting synergistically with the GFAP-ϵR430H mutation, conditioning the development of the severe MND phenotype of Pt2.\nThe mechanisms underlying the diverse etiology and expressivity of many inherited neurodegenerative disorders are still poorly understood. Exome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression and penetrance."}

{"project":"2_test","denotations":[{"id":"23634874-18684770-81641091","span":{"begin":240,"end":241},"obj":"18684770"},{"id":"23634874-18388212-81641092","span":{"begin":730,"end":732},"obj":"18388212"},{"id":"23634874-12024216-81641093","span":{"begin":1894,"end":1896},"obj":"12024216"},{"id":"23634874-20404488-81641094","span":{"begin":2234,"end":2236},"obj":"20404488"},{"id":"23634874-22372633-81641095","span":{"begin":2237,"end":2239},"obj":"22372633"},{"id":"23634874-20720006-81641096","span":{"begin":2434,"end":2436},"obj":"20720006"},{"id":"23634874-19910924-81641097","span":{"begin":2521,"end":2523},"obj":"19910924"},{"id":"23634874-17568747-81641098","span":{"begin":2637,"end":2638},"obj":"17568747"},{"id":"23634874-20940043-81641099","span":{"begin":2816,"end":2818},"obj":"20940043"},{"id":"23634874-22372633-81641100","span":{"begin":2902,"end":2904},"obj":"22372633"},{"id":"23634874-18180281-81641101","span":{"begin":3025,"end":3027},"obj":"18180281"},{"id":"23634874-22328923-81641102","span":{"begin":3129,"end":3131},"obj":"22328923"},{"id":"23634874-20075865-81641103","span":{"begin":3323,"end":3325},"obj":"20075865"},{"id":"23634874-21377170-81641104","span":{"begin":3499,"end":3500},"obj":"21377170"},{"id":"23634874-22372633-81641105","span":{"begin":3501,"end":3503},"obj":"22372633"},{"id":"23634874-23184605-81641106","span":{"begin":3504,"end":3506},"obj":"23184605"},{"id":"23634874-21377170-81641107","span":{"begin":3619,"end":3620},"obj":"21377170"},{"id":"T96897","span":{"begin":240,"end":241},"obj":"18684770"},{"id":"T44180","span":{"begin":730,"end":732},"obj":"18388212"},{"id":"T33708","span":{"begin":1894,"end":1896},"obj":"12024216"},{"id":"T5517","span":{"begin":2234,"end":2236},"obj":"20404488"},{"id":"T29199","span":{"begin":2237,"end":2239},"obj":"22372633"},{"id":"T48287","span":{"begin":2434,"end":2436},"obj":"20720006"},{"id":"T87280","span":{"begin":2521,"end":2523},"obj":"19910924"},{"id":"T45541","span":{"begin":2637,"end":2638},"obj":"17568747"},{"id":"T33489","span":{"begin":2816,"end":2818},"obj":"20940043"},{"id":"T15726","span":{"begin":2902,"end":2904},"obj":"22372633"},{"id":"T48149","span":{"begin":3025,"end":3027},"obj":"18180281"},{"id":"T65385","span":{"begin":3129,"end":3131},"obj":"22328923"},{"id":"T39909","span":{"begin":3323,"end":3325},"obj":"20075865"},{"id":"T10435","span":{"begin":3499,"end":3500},"obj":"21377170"},{"id":"T16572","span":{"begin":3501,"end":3503},"obj":"22372633"},{"id":"T60470","span":{"begin":3504,"end":3506},"obj":"23184605"},{"id":"T66386","span":{"begin":3619,"end":3620},"obj":"21377170"}],"text":"Discussion\nA substantial fraction of AOAD patients are sporadic, the most frequent symptoms being related to bulbar dysfunction, pyramidal involvement and cerebellar ataxia. Palatal myoclonus is frequent in, and highly suggestive of, AOAD [4]. Other findings include cognitive deterioration, sleep disorders, and dysautonomia. The course is slowly progressive and fluctuations may occur. Ultimately, the diagnosis is strongly suggested by a typical MRI pattern, and confirmed by GFAP gene analysis. In our family, Pt1 has been suffering of slowly progressive cognitive impairment and mild movement disorder, whereas her younger half-brother (Pt2) has severe MND. In spite of clinical diversity, the cardinal MRI features of AOAD [24] were present in both. The absence of mutation in the GFAP-α encoding gene prompted us to perform exome-NGS and eventually identify a unique mutation in alternative GFAP ex7A, not present in the healthy mother tested DNAs and with a deleterious outcome in a cellular model. These are in fact the first cases associated with a mutation in the GFAP-ϵ variant (GFAP-ϵR430H). Whilst this finding supports the idea that AOAD is almost invariably associated with abnormalities of GFAP, it also expands the spectrum of variants that should be included in the diagnostic screening. Due to the pedigree structure, the mutation has very likely been transmitted by maternal germinal mosaicism, since it was absent in other available family members, including the healthy mother of the two patients.\nThe clinical diversity in our two half-siblings was as remarkable as to suggest that differential segregation of other gene variants could influence phenotypic expression. A prioritized variant found by in-silico data mining was in HDAC6. A hemizygous HDAC6P856S change, found in Pt2, and absent in Pt1, was associated with decreased tubulin-specific deacetylase activity [22]. Through deacetylation of α-tubulin, HSP90, and other substrates, and binding to ubiquitinated proteins that are then transported into, and degraded by, the aggresome, HDAC6 plays a role in a number of important homeostatic and signaling pathways, including axonal transport, redox signaling, misfolded-protein response, and autophagy [25,26]. Interestingly, the RNA-binding modulator factors TDP-43 and FUS/TLS, whose mutations are associated with familial amyotrophic lateral sclerosis (ALS), have HDAC6 mRNA as a specific substrate [27]. A Drosophila model in which TDP-43 is silenced shows decreased HDAC6 expression, [28] and HDAC6 overexpression is able to rescue the phenotype of a Drosophila model of spinobulbar muscular atrophy [6].\nTaken together, these observations indicate HDAC6 as a master regulator of different neuroprotective mechanisms, partly mediated by controlling MTOC biogenesis and function, [23] and predict a role for defective HDAC6 in neurodegeneration, particularly in MND [26]. As for mammalian models, although a first strain of HDAC6 knockout (KO) mice presented no sign of neurodegeneration, [29] altered emotional behaviors suggested a contribution of HDAC6 to maintain proper neuronal activity [30]. Moreover, a second KO HDAC6 strain displayed ubiquitin-positive aggregates and increased apoptosis of brain nerve cells, both hallmarks of neurodegeneration, starting from 6 months of age [31]. These and other results suggest for HDAC6 a complex role in contributing to either neuroprotection or neurodegeneration, depending on the specific pathological condition [7,26,32]. These opposite effects can indeed hamper the development of therapeutic strategies based on HDAC6 modulation [7].\nAlbeit preliminary, our own results support the interesting hypothesis that the HDAC6P856S protein variant may be acting synergistically with the GFAP-ϵR430H mutation, conditioning the development of the severe MND phenotype of Pt2.\nThe mechanisms underlying the diverse etiology and expressivity of many inherited neurodegenerative disorders are still poorly understood. Exome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression and penetrance."}