A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations
Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment f...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Valcárcel-Hernández, Víctor [verfasserIn] |
|---|
| Format: |
E-Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2022transfer abstract |
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| Übergeordnetes Werk: |
Enthalten in: Rational administration sequencing of immunochemotherapy elicits powerful anti-tumor effect - Zhu, Chunqi ELSEVIER, 2021, Orlando, Fla |
|---|---|
| Übergeordnetes Werk: |
volume:174 ; year:2022 ; pages:0 |
| Links: |
|---|
| DOI / URN: |
10.1016/j.nbd.2022.105896 |
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| 520 | |a Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. | ||
| 520 | |a Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. | ||
| 700 | 1 | |a Guillén-Yunta, Marina |4 oth | |
| 700 | 1 | |a Bueno-Arribas, Miranda |4 oth | |
| 700 | 1 | |a Montero-Pedrazuela, Ana |4 oth | |
| 700 | 1 | |a Grijota-Martínez, Carmen |4 oth | |
| 700 | 1 | |a Markossian, Suzy |4 oth | |
| 700 | 1 | |a García-Aldea, Ángel |4 oth | |
| 700 | 1 | |a Flamant, Frédéric |4 oth | |
| 700 | 1 | |a Bárez-López, Soledad |4 oth | |
| 700 | 1 | |a Guadaño-Ferraz, Ana |4 oth | |
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10.1016/j.nbd.2022.105896 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001991.pica (DE-627)ELV059309164 (ELSEVIER)S0969-9961(22)00288-1 DE-627 ger DE-627 rakwb eng 540 610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl 58.28 bkl Valcárcel-Hernández, Víctor verfasserin aut A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. Guillén-Yunta, Marina oth Bueno-Arribas, Miranda oth Montero-Pedrazuela, Ana oth Grijota-Martínez, Carmen oth Markossian, Suzy oth García-Aldea, Ángel oth Flamant, Frédéric oth Bárez-López, Soledad oth Guadaño-Ferraz, Ana oth Enthalten in Academic Press Zhu, Chunqi ELSEVIER Rational administration sequencing of immunochemotherapy elicits powerful anti-tumor effect 2021 Orlando, Fla (DE-627)ELV007282540 volume:174 year:2022 pages:0 https://doi.org/10.1016/j.nbd.2022.105896 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-PHARM SSG-OLC-PHA SSG-OPC-PHA 44.40 Pharmazie Pharmazeutika VZ 58.28 Pharmazeutische Technologie VZ AR 174 2022 0 |
| spelling |
10.1016/j.nbd.2022.105896 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001991.pica (DE-627)ELV059309164 (ELSEVIER)S0969-9961(22)00288-1 DE-627 ger DE-627 rakwb eng 540 610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl 58.28 bkl Valcárcel-Hernández, Víctor verfasserin aut A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. Guillén-Yunta, Marina oth Bueno-Arribas, Miranda oth Montero-Pedrazuela, Ana oth Grijota-Martínez, Carmen oth Markossian, Suzy oth García-Aldea, Ángel oth Flamant, Frédéric oth Bárez-López, Soledad oth Guadaño-Ferraz, Ana oth Enthalten in Academic Press Zhu, Chunqi ELSEVIER Rational administration sequencing of immunochemotherapy elicits powerful anti-tumor effect 2021 Orlando, Fla (DE-627)ELV007282540 volume:174 year:2022 pages:0 https://doi.org/10.1016/j.nbd.2022.105896 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-PHARM SSG-OLC-PHA SSG-OPC-PHA 44.40 Pharmazie Pharmazeutika VZ 58.28 Pharmazeutische Technologie VZ AR 174 2022 0 |
| allfields_unstemmed |
10.1016/j.nbd.2022.105896 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001991.pica (DE-627)ELV059309164 (ELSEVIER)S0969-9961(22)00288-1 DE-627 ger DE-627 rakwb eng 540 610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl 58.28 bkl Valcárcel-Hernández, Víctor verfasserin aut A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. Guillén-Yunta, Marina oth Bueno-Arribas, Miranda oth Montero-Pedrazuela, Ana oth Grijota-Martínez, Carmen oth Markossian, Suzy oth García-Aldea, Ángel oth Flamant, Frédéric oth Bárez-López, Soledad oth Guadaño-Ferraz, Ana oth Enthalten in Academic Press Zhu, Chunqi ELSEVIER Rational administration sequencing of immunochemotherapy elicits powerful anti-tumor effect 2021 Orlando, Fla (DE-627)ELV007282540 volume:174 year:2022 pages:0 https://doi.org/10.1016/j.nbd.2022.105896 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-PHARM SSG-OLC-PHA SSG-OPC-PHA 44.40 Pharmazie Pharmazeutika VZ 58.28 Pharmazeutische Technologie VZ AR 174 2022 0 |
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10.1016/j.nbd.2022.105896 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001991.pica (DE-627)ELV059309164 (ELSEVIER)S0969-9961(22)00288-1 DE-627 ger DE-627 rakwb eng 540 610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl 58.28 bkl Valcárcel-Hernández, Víctor verfasserin aut A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. Guillén-Yunta, Marina oth Bueno-Arribas, Miranda oth Montero-Pedrazuela, Ana oth Grijota-Martínez, Carmen oth Markossian, Suzy oth García-Aldea, Ángel oth Flamant, Frédéric oth Bárez-López, Soledad oth Guadaño-Ferraz, Ana oth Enthalten in Academic Press Zhu, Chunqi ELSEVIER Rational administration sequencing of immunochemotherapy elicits powerful anti-tumor effect 2021 Orlando, Fla (DE-627)ELV007282540 volume:174 year:2022 pages:0 https://doi.org/10.1016/j.nbd.2022.105896 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-PHARM SSG-OLC-PHA SSG-OPC-PHA 44.40 Pharmazie Pharmazeutika VZ 58.28 Pharmazeutische Technologie VZ AR 174 2022 0 |
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10.1016/j.nbd.2022.105896 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001991.pica (DE-627)ELV059309164 (ELSEVIER)S0969-9961(22)00288-1 DE-627 ger DE-627 rakwb eng 540 610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl 58.28 bkl Valcárcel-Hernández, Víctor verfasserin aut A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. Guillén-Yunta, Marina oth Bueno-Arribas, Miranda oth Montero-Pedrazuela, Ana oth Grijota-Martínez, Carmen oth Markossian, Suzy oth García-Aldea, Ángel oth Flamant, Frédéric oth Bárez-López, Soledad oth Guadaño-Ferraz, Ana oth Enthalten in Academic Press Zhu, Chunqi ELSEVIER Rational administration sequencing of immunochemotherapy elicits powerful anti-tumor effect 2021 Orlando, Fla (DE-627)ELV007282540 volume:174 year:2022 pages:0 https://doi.org/10.1016/j.nbd.2022.105896 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-PHARM SSG-OLC-PHA SSG-OPC-PHA 44.40 Pharmazie Pharmazeutika VZ 58.28 Pharmazeutische Technologie VZ AR 174 2022 0 |
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Valcárcel-Hernández, Víctor @@aut@@ Guillén-Yunta, Marina @@oth@@ Bueno-Arribas, Miranda @@oth@@ Montero-Pedrazuela, Ana @@oth@@ Grijota-Martínez, Carmen @@oth@@ Markossian, Suzy @@oth@@ García-Aldea, Ángel @@oth@@ Flamant, Frédéric @@oth@@ Bárez-López, Soledad @@oth@@ Guadaño-Ferraz, Ana @@oth@@ |
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Valcárcel-Hernández, Víctor |
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a crispr/cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations |
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A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations |
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Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. |
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Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. |
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Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency. |
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