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Hum Genet. 2005 Jan;116(1-2):114-20. Epub 2004 Nov 17.

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

Author information

1
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

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.

PMID:
15599766
DOI:
10.1007/s00439-004-1192-9
[Indexed for MEDLINE]

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