Human Genetics

, Volume 116, Issue 1–2, pp 114–120 | Cite as

A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia

  • Samuel Canizales-Quinteros
  • Carlos A. Aguilar-Salinas
  • Adriana Huertas-Vázquez
  • María L. Ordóñez-Sánchez
  • Maribel Rodríguez-Torres
  • José L. Venturas-Gallegos
  • Laura Riba
  • Salvador Ramírez-Jimenez
  • Rocío Salas-Montiel
  • Giovani Medina-Palacios
  • Ludivina Robles-Osorio
  • Angel Miliar-García
  • Luis Rosales-León
  • Blanca H. Ruiz-Ordaz
  • Alejandro Zentella-Dehesa
  • Adrian Ferré-D’Amare
  • Francisco J. Gómez-Pérez
  • Ma. Teresa. Tusié-Luna
Original Investigation

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 β-strands β6 and β7 from the PTB domain. This is the first case where a naturally occurring mutant with an altered PTB domain has been identified.

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Samuel Canizales-Quinteros
    • 1
  • Carlos A. Aguilar-Salinas
    • 2
  • Adriana Huertas-Vázquez
    • 1
  • María L. Ordóñez-Sánchez
    • 2
  • Maribel Rodríguez-Torres
    • 1
  • José L. Venturas-Gallegos
    • 3
  • Laura Riba
    • 1
  • Salvador Ramírez-Jimenez
    • 1
  • Rocío Salas-Montiel
    • 1
  • Giovani Medina-Palacios
    • 4
  • Ludivina Robles-Osorio
    • 2
  • Angel Miliar-García
    • 5
  • Luis Rosales-León
    • 4
  • Blanca H. Ruiz-Ordaz
    • 4
  • Alejandro Zentella-Dehesa
    • 3
  • Adrian Ferré-D’Amare
    • 6
  • Francisco J. Gómez-Pérez
    • 2
  • Ma. Teresa. Tusié-Luna
    • 1
  1. 1.Unidad de Biología Molecular y Medicina GenómicaInstituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán”Mexico CityMexico
  2. 2.Departamento de Endocrinología y Metabolismo de LípidosInstituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico CityMexico
  3. 3.Departamento de Biología Celular, Instituto de Fisiología CelularUniversidad Nacional Autónoma de MéxicoMexico CityMexico
  4. 4.Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoMexico CityMexico
  5. 5.Sección de Estudios de Posgrado e Investigación, Escuela Superior de MedicinaInstituto Politécnico NacionalMexico CityMexico
  6. 6.Division of Basic SciencesFred Hutchinson Cancer Research CenterSeattleUSA

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