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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Acknowledgements
We are grateful to the family who participated in this study. This work was supported by Consejo Nacional de Ciencia y Tecnología (CONACyT) (30774-M), Dirección General de Asuntos del Personal Académico, UNAM (IN217501) and Fundación Miguel Alemán (Mexico). A.H.-V. and L.R.-O. were supported by a fellowship from CONACyT.
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Canizales-Quinteros, S., Aguilar-Salinas, C.A., Huertas-Vázquez, A. et al. A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia. Hum Genet 116, 114–120 (2005). https://doi.org/10.1007/s00439-004-1192-9
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DOI: https://doi.org/10.1007/s00439-004-1192-9