A variant in GRN of Spanish origin presenting with heterogeneous phenotypes
Introduction: The variant c.1414-1G>T in the GRN gene has previously been reported as probably pathogenic in subjects of Hispanic origin in the American continent. Methods: We report 5 families of Spanish origin carrying this variant, including the clinical, neuroimaging, and laboratory findings....
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Elsevier España
2025-01-01
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| Series: | Neurología (English Edition) |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2173580822001122 |
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| author | M. Menéndez-González A. García-Martínez I. Fernández-Vega A. Pitiot V. Álvarez |
| author_facet | M. Menéndez-González A. García-Martínez I. Fernández-Vega A. Pitiot V. Álvarez |
| author_sort | M. Menéndez-González |
| collection | DOAJ |
| description | Introduction: The variant c.1414-1G>T in the GRN gene has previously been reported as probably pathogenic in subjects of Hispanic origin in the American continent. Methods: We report 5 families of Spanish origin carrying this variant, including the clinical, neuroimaging, and laboratory findings. Results: Phenotypes were strikingly different, including cases presenting with behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, rapidly progressive motor neuron disease (pathologically documented), and tremor-dominant parkinsonism. Retinal degeneration has been found in homozygous carriers only. Ex vivo splicing assays confirmed that the mutation c.1414-1G>T affects the splicing of the exon, causing a loss of 20 amino acids in exon 11. Conclusions: We conclude that variant c.1414-1G>T of the GRN gene is pathogenic, can lead to a variety of clinical presentations and to gene dosage effect, and probably has a Spanish founder effect. Resumen: Introducción: La variante c.1414-1G > T en el gen GRN ha sido reportada previamente como probablemente patogénica en sujetos del continente Americano de origen Hispano. Métodos: Reportamos cinco familias de origen Español portadoras de la mencionada variante. Se presentan las características clínicas, de neuroimagen y de laboratorio. Resultados: Los fenotipos encontrados difieren llamativamente entre los distintos casos, incluyendo presentación como demencia frontotemporal variante conductual, variante semántica de afasia progresiva primaria, enfermedad de neurona motora rápidamente progresiva (con confirmación neuropatológico) y parkinsonismo de predominio tremórico. Degeneración retiniana fue evidenciada únicamente en portadores homocigotos. Ensayos de splicing ex vivo confirman que la mutación c.1414-1G > T afecta el splicing del exón, causando una pérdida de 20 aminoácidos en el exón 11. Conclusiones: Concluimos que la variante c.1414-1G > T del gen GRN es patogénica, puede causar presentaciones clínicas diversas, efecto de dosis génica y probablemente represente un efecto fundador de origen Español. |
| format | Article |
| id | doaj-art-61b8a0d64ec14a34baed3afbfed7950d |
| institution | Kabale University |
| issn | 2173-5808 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier España |
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| spelling | doaj-art-61b8a0d64ec14a34baed3afbfed7950d2025-01-26T05:03:45ZengElsevier EspañaNeurología (English Edition)2173-58082025-01-014015765A variant in GRN of Spanish origin presenting with heterogeneous phenotypesM. Menéndez-González0A. García-Martínez1I. Fernández-Vega2A. Pitiot3V. Álvarez4Department of Neurology, Hospital Universitario Central de Asturias, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Spain; Department of Medicine, Universidad de Oviedo, Spain; Corresponding author.Department of Neurology, Hospital Universitario Central de Asturias, SpainInstituto de Investigación Sanitaria del Principado de Asturias (ISPA), Spain; Department of Pathology Anatomy, Hospital Universitario Central de Asturias, Spain; Department of Surgery, Universidad de Oviedo, SpainLaboratory of Molecular Oncology, Hospital Universitario Central de Asturias, SpainInstituto de Investigación Sanitaria del Principado de Asturias (ISPA), Spain; Laboratory of Genetics, Hospital Universitario Central de Asturias, SpainIntroduction: The variant c.1414-1G>T in the GRN gene has previously been reported as probably pathogenic in subjects of Hispanic origin in the American continent. Methods: We report 5 families of Spanish origin carrying this variant, including the clinical, neuroimaging, and laboratory findings. Results: Phenotypes were strikingly different, including cases presenting with behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, rapidly progressive motor neuron disease (pathologically documented), and tremor-dominant parkinsonism. Retinal degeneration has been found in homozygous carriers only. Ex vivo splicing assays confirmed that the mutation c.1414-1G>T affects the splicing of the exon, causing a loss of 20 amino acids in exon 11. Conclusions: We conclude that variant c.1414-1G>T of the GRN gene is pathogenic, can lead to a variety of clinical presentations and to gene dosage effect, and probably has a Spanish founder effect. Resumen: Introducción: La variante c.1414-1G > T en el gen GRN ha sido reportada previamente como probablemente patogénica en sujetos del continente Americano de origen Hispano. Métodos: Reportamos cinco familias de origen Español portadoras de la mencionada variante. Se presentan las características clínicas, de neuroimagen y de laboratorio. Resultados: Los fenotipos encontrados difieren llamativamente entre los distintos casos, incluyendo presentación como demencia frontotemporal variante conductual, variante semántica de afasia progresiva primaria, enfermedad de neurona motora rápidamente progresiva (con confirmación neuropatológico) y parkinsonismo de predominio tremórico. Degeneración retiniana fue evidenciada únicamente en portadores homocigotos. Ensayos de splicing ex vivo confirman que la mutación c.1414-1G > T afecta el splicing del exón, causando una pérdida de 20 aminoácidos en el exón 11. Conclusiones: Concluimos que la variante c.1414-1G > T del gen GRN es patogénica, puede causar presentaciones clínicas diversas, efecto de dosis génica y probablemente represente un efecto fundador de origen Español.http://www.sciencedirect.com/science/article/pii/S2173580822001122GranulinaDemencia frontotemporalEnfermedad de motoneuronaParkinsonismoAfasia progresiva primariaDegeneración retiniana |
| spellingShingle | M. Menéndez-González A. García-Martínez I. Fernández-Vega A. Pitiot V. Álvarez A variant in GRN of Spanish origin presenting with heterogeneous phenotypes Neurología (English Edition) Granulina Demencia frontotemporal Enfermedad de motoneurona Parkinsonismo Afasia progresiva primaria Degeneración retiniana |
| title | A variant in GRN of Spanish origin presenting with heterogeneous phenotypes |
| title_full | A variant in GRN of Spanish origin presenting with heterogeneous phenotypes |
| title_fullStr | A variant in GRN of Spanish origin presenting with heterogeneous phenotypes |
| title_full_unstemmed | A variant in GRN of Spanish origin presenting with heterogeneous phenotypes |
| title_short | A variant in GRN of Spanish origin presenting with heterogeneous phenotypes |
| title_sort | variant in grn of spanish origin presenting with heterogeneous phenotypes |
| topic | Granulina Demencia frontotemporal Enfermedad de motoneurona Parkinsonismo Afasia progresiva primaria Degeneración retiniana |
| url | http://www.sciencedirect.com/science/article/pii/S2173580822001122 |
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