title: A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia.
abstract: Autosomal recessive hypercholesterolemia (ARH) is characterized by elevated LDL serum levels, xanthomatosis, and premature coronary artery disease. Three loci have been described for this condition (1p35, 15q25-q26 and 13q). Recently, the responsible gene at the 1p35 locus, encoding an LDL receptor adaptor protein (ARH) has been identified. We studied a Mexican ARH family with two affected siblings. Sequence analysis of the ARH gene (1p35 locus) revealed that the affected siblings are homozygous for a novel mutation (IVS4+2T>G) affecting the donor splice site in intron 4, whereas both the parents and an unaffected sister are heterozygous for this mutation. The IVS4+2T>G mutation results in a major alternative transcript derived from a cryptic splice site, which carries an in-frame deletion of 78 nucleotides in the mature mRNA. The translation of this mRNA yields a mutant protein product (ARH-26) lacking 26 amino acids, resulting in the loss of beta-strands beta6 and beta7 from the PTB domain. This is the first case where a naturally occurring mutant with an altered PTB domain has been identified.
authors.affiliation: Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán", Vasco de Quiroga #15 Colonia Sección 16, Mexico City, 14000 Tlalpan, Mexico. cani@servidor.unam.mx
authors.forename: Samuel
authors.initials: S
authors.lastname: Canizales-Quinteros
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Aguilar-Salinas
authors.forename: Adriana
authors.initials: A
authors.lastname: Huertas-Vázquez
authors.forename: María L
authors.initials: ML
authors.lastname: Ordóñez-Sánchez
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodríguez-Torres
authors.forename: José L
authors.initials: JL
authors.lastname: Venturas-Gallegos
authors.forename: Laura
authors.initials: L
authors.lastname: Riba
authors.forename: Salvador
authors.initials: S
authors.lastname: Ramírez-Jimenez
authors.forename: Rocío
authors.initials: R
authors.lastname: Salas-Montiel
authors.forename: Giovani
authors.initials: G
authors.lastname: Medina-Palacios
authors.forename: Ludivina
authors.initials: L
authors.lastname: Robles-Osorio
authors.forename: Angel
authors.initials: A
authors.lastname: Miliar-García
authors.forename: Luis
authors.initials: L
authors.lastname: Rosales-León
authors.forename: Blanca H
authors.initials: BH
authors.lastname: Ruiz-Ordaz
authors.forename: Alejandro
authors.initials: A
authors.lastname: Zentella-Dehesa
authors.forename: Adrian
authors.initials: A
authors.lastname: Ferré-D'Amare
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Gómez-Pérez
authors.forename: Ma Teresa
authors.initials: MT
authors.lastname: Tusié-Luna
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D003241:Consanguinity; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008800:Mexico; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017434:Protein Structure, Tertiary; D022821:RNA Splice Sites / Q000235:genetics*; D014973:Xanthomatosis / Q000235:genetics / Q000503:physiopathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C469745:LDLRAP1 protein, human; D022821:RNA Splice Sites