First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants.

Autor: Reyna-Fabián ME; Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, México., Hernández-Martínez NL; Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, México., Alcántara-Ortigoza MA; Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, México., Ayala-Sumuano JT; IDIX SA de CV., Querétaro, México., Enríquez-Flores S; Grupo de Investigación en Biomoléculas y Salud Infantil, Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Ciudad de México, México., Velázquez-Aragón JA; Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, México., Varela-Echavarría A; Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México., Todd-Quiñones CG; Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México, México.; Laboratorio de Biología Molecular, Departamento de Genética Humana, Hospital de Alta Especialidad de Veracruz, Veracruz, México., González-Del Angel A; Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, México. ariadnagonzalezdelangel@gmail.com.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2020 Apr 20; Vol. 10 (1), pp. 6589. Date of Electronic Publication: 2020 Apr 20.
DOI: 10.1038/s41598-020-62759-5
Abstrakt: 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.
Databáze: MEDLINE
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