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ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele

Authors
  • González-Domínguez, Carlos Alberto1, 2
  • Fiesco-Roa, Moisés O.3, 4
  • Gómez-Carmona, Samuel5
  • Kleinert-Altamirano, Anke Paula Ingrid5, 6
  • He, Miao7
  • Daniel, Earnest James Paul7
  • Raymond, Kimiyo M.8
  • Abreu-González, Melania9
  • Manrique-Hernández, Sandra1, 2
  • González-Jaimes, Ana1
  • Salinas-Marín, Roberta1
  • Molina-Garay, Carolina10
  • Carrillo-Sánchez, Karol10
  • Flores-Lagunes, Luis Leonardo10
  • Jiménez-Olivares, Marco10
  • Muñoz-Rivas, Anallely10
  • Cruz-Muñoz, Mario E.11
  • Ruíz-García, Matilde12
  • Freeze, Hudson H.13
  • Mora-Montes, Héctor M.14
  • And 2 more
  • 1 Laboratorio de Glicobiología Humana y Diagnóstico Molecular, Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca , (Mexico)
  • 2 Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca , (Mexico)
  • 3 Programa de Maestría y Doctorado en Ciencias Médicas, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Mexico City , (Mexico)
  • 4 Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City , (Mexico)
  • 5 Centro de Rehabilitación e Inclusión Infantil Teletón, Tuxtla Gutiérrez , (Mexico)
  • 6 Palmieri Metabolic Disease Laboratory, Children’s Hospital of Philadelphia, Philadelphia, PA , (United States)
  • 7 Hospital Regional de Alta Especialidad Ciudad Salud, Tapachula , (Mexico)
  • 8 Department of Laboratory Medicine and Pathology, Laboratory Genetics and Genomics, Mayo Clinic, Rochester, MN , (United States)
  • 9 Genos Médica, Mexico City , (Mexico)
  • 10 Laboratorio de Diagnóstico Genómico, Instituto Nacional de Medicina Genómica, Secretaría de Salud, Mexico City , (Mexico)
  • 11 Laboratorio de Inmunología Molecular, Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca , (Mexico)
  • 12 Departamento de Neurología, Instituto Nacional de Pediatría, Mexico City , (Mexico)
  • 13 Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA , (United States)
  • 14 Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato , (Mexico)
  • 15 Sociedad Latinoamericana de Glicobiología A.C., Cuernavaca , (Mexico)
Type
Published Article
Journal
Frontiers in Genetics
Publisher
Frontiers Media SA
Publication Date
Sep 09, 2021
Volume
12
Identifiers
DOI: 10.3389/fgene.2021.744884
PMID: 34567092
PMCID: PMC8458739
Source
PubMed Central
Keywords
Disciplines
  • Genetics
  • Original Research
License
Unknown

Abstract

This study reports on a Mexican mestizo patient with a multi-systemic syndrome including neurological involvement and a type I serum transferrin profile. Clinical exome sequencing revealed complex alleles in ALG1 , the encoding gene for the chitobiosyldiphosphodolichol beta-mannosyltransferase that participates in the formation of the dolichol-pyrophosphate-GlcNAc2Man5, a lipid-linked glycan intermediate during N -glycan synthesis. The identified complex alleles were NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 208 + 25G > T] and NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 1312C > T]. Although both alleles carried the benign variant c.208 + 16_208 + 19dup, one allele carried a known ALG1 pathogenic variant (c.1312C > T), while the other carried a new uncharacterized variant (c.208 + 25G > T) causing non-functional alternative splicing that, in conjunction with the benign variant, defines the pathogenic protein effect (p.N70S_S71ins9). The presence in the patient’s serum of the pathognomonic N-linked mannose-deprived tetrasaccharide marker for ALG1-CDG (Neu5Acα2,6Galβ1,4-GlcNAcβ1,4GlcNAc) further supported this diagnosis. This is the first report of an ALG1-CDG patient from Latin America.

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