First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants
Por:
Reyna-Fabian, Miriam E., Hernandez-Martinez, Nancy L., Alcantara-Ortigoza, Miguel A., Ayala-Sumuano, Jorge T., Enriquez-Flores, Sergio, Velazquez-Aragon, Jose A., Varela-Echavarria, Alfredo, Todd-Quinones, Carlos G., Gonzalez-del Angel, Ariadna
Publicada:
1 ene 2020
Categoría:
Multidisciplinary
Resumen:
The aim of this study was to improve knowledge of the mutational spectrum causing tuberous sclerosis complex (TSC) in a sample of Mexican patients, given the limited information available regarding this disease in Mexico and Latin America. Four different molecular techniques were implemented to identify from single nucleotide variants to large rearrangements in the TSC1 and TSC2 genes of 66 unrelated Mexican-descent patients that clinically fulfilled the criteria for a definitive TSC diagnosis. The mutation detection rate was 94%, TSC2 pathogenic variants (PV) prevailed over TSC1 PV (77% vs. 23%) and a recurrent mutation site (hotspot) was observed in TSC1 exon 15. Interestingly, 40% of the identified mutations had not been previously reported. The wide range of novels PV made it difficult to establish any genotype-phenotype correlation, but most of the PV conditioned neurological involvement (intellectual disability and epilepsy). Our 3D protein modeling of two variants classified as likely pathogenic demonstrated that they could alter the structure and function of the hamartin (TSC1) or tuberin (TSC2) proteins. Molecular analyses of parents and first-degree affected family members of the index cases enabled us to distinguish familial (18%) from sporadic (82%) cases and to identify one case of apparent gonadal mosaicism. © 2020, The Author(s).
Filiaciones:
Reyna-Fabian, Miriam E.:
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, Mexico
Secretaria Salud, Lab Biol Mol, Inst Nacl Pediat, Ciudad De Mexico, Mexico
Hernandez-Martinez, Nancy L.:
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, Mexico
Secretaria Salud, Lab Biol Mol, Inst Nacl Pediat, Ciudad De Mexico, Mexico
Alcantara-Ortigoza, Miguel A.:
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, Mexico
Secretaria Salud, Lab Biol Mol, Inst Nacl Pediat, Ciudad De Mexico, Mexico
Ayala-Sumuano, Jorge T.:
IDIX SA de CV., Querétaro, Mexico
IDIX SA CV, Queretaro, Mexico
Enriquez-Flores, Sergio:
Grupo de Investigación en Biomoléculas y Salud Infantil, Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Ciudad de México, Mexico
Inst Nacl Pediat, Grp Invest Biomol & Salud Infantil, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico, Mexico
Velazquez-Aragon, Jose A.:
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, Mexico
Secretaria Salud, Lab Biol Mol, Inst Nacl Pediat, Ciudad De Mexico, Mexico
Varela-Echavarria, Alfredo:
Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico
Univ Nacl Autonoma Mexico, Inst Neurobiol, Dept Neurobiol Desarrollo & Neurofisiol, Queretaro, Mexico
Todd-Quinones, Carlos G.:
Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México, Mexico
Laboratorio de Biología Molecular, Departamento de Genética Humana, Hospital de Alta Especialidad de Veracruz, Veracruz, Mexico
Univ Autonoma Metropolitana Iztapalapa, Posgrad Biol Expt, Ciudad De Mexico, Mexico
Hosp Alta Especialidad Veracruz, Dept Genet Humana, Lab Biol Mol, Veracruz, Veracruz, Mexico
Gonzalez-del Angel, Ariadna:
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, Mexico
Secretaria Salud, Lab Biol Mol, Inst Nacl Pediat, Ciudad De Mexico, Mexico
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